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With the recent release of ENDF/B VIII.0 data, additional covariance data was provided for many isotopes, including O16. The detail of elastic scattering and mubar covariance data for O16 increased dramatically between ENDF/B VII.1 and ENDF/B VIII.0. This new covariance data has been processed with NJOY2016 and investigation has begun on the effects of these new uncertainty data. The uncertainties are applied to multi-group scattering cross sections and P1 Legendre components in deterministic neutron transport. A simple but typical application of shielding fission neutrons with concrete has been used to assess the practical effects of the new covariance data for O16. A somewhat surprising result is that the mubar uncertainty can have a significant effect on the calculated shielding and criticality results.

There is increasing awareness worldwide that traditional flood-mitigation strategies that attempt to control the flow of water only increase the likelihood of catastrophic consequences in the long run, when failure inevitably occurs after years of complacency and development behind flood barriers. Amphibious architecture is a non-defensive flood mitigation and climate change adaptation strategy that works in synchrony with a floodprone region’s natural cycles of flooding, allowing water to flow rather than creating an obstruction. Since the height to which an amphibious building rises is not necessarily fixed but adapts to the variable depth of flood water, amphibiation can accommodate rising sea levels and land subsidence as well. Amphibious retrofitting can provide measurable cost savings compared to other flood mitigation strategies, performing well in loss avoidance studies for both flood and wind damage. An amphibious approach to planning and construction recognizes the beneficial aspects of seasonal and occasional flooding, allowing us not merely to live with water, but to thrive with it. This paper reviews case studies of both existing and proposed amphibious buildings, with discussion of their systems and components. It also discusses the limitations of amphibious construction, some of the regulatory obstacles that have discouraged its development, and possible paths forward. The first International Conference on Amphibious Architecture, Design and Engineering, ICAADE 2015, was held in Bangkok, Thailand, in August 2015. The second, ICAADE 2017, will convene at the University of Waterloo in Canada in June 2017.

Abstract Background The composition of dietary fatty acids (FA) during early life may impact adult adipose tissue (AT) development. We investigated the effects of α-linolenic acid (ALA) intake during the suckling/weaning period on AT development and metabolic markers in the guinea pig (GP). Methods Newborn GP were fed a 27%-fat diet (w/w %) with high (10%-ALA group), moderate (2.4%-ALA group) or low (0.8%-ALA group) ALA content (w/w % as total FA) until they were 21 days old (d21). Then all animals were switched to a 15%-fat diet containing 2% ALA (as total FA) until 136 days of age (d136). Results ALA and docosapentaenoic acid measured in plasma triglycerides (TG) at d21 decreased with decreasing ALA intake. Total body fat mass was not different between groups at d21. Adipose tissue TG synthesis rates and proliferation rate of total adipose cells, as assessed by 2H2O labelling, were unchanged between groups at d21, while hepatic de novo lipogenesis was significantly 2-fold increased in the 0.8%-ALA group. In older GP, the 0.8%-ALA group showed a significant 15-%-increased total fat mass (d79 and d107, p < 0.01) and epididymal AT weight (d136) and tended to show higher insulinemia compared to the 10%-ALA group. In addition, proliferation rate of cells in the subcutaneous AT was higher in the 0.8%-ALA (15.2 ± 1.3% new cells/5d) than in the 10%-ALA group (8.6 ± 1.7% new cells/5d, p = 0.021) at d136. AT eicosanoid profiles were not associated with the increase of AT cell proliferation. Conclusion A low ALA intake during early postnatal life promotes an increased adiposity in the adult GP.

Background: The intersection of race/ethnicity with disability is a critical dimension of mental health outcomes in later ages that remains under-investigated., Objective: We examined the role of race-ethnicity in moderating the associations between functional disabilities and subsequent depression among Americans 51 and older and stratified into the two age-groups of midlife (51-64) and older adults (≥65)., Methods: Using a nationally representative sample of community-dwelling Americans (≥51; n = 7475) in the 2016-2018 Health and Retirement Study, we conducted bivariate and multivariable regression analyses. Racial-ethnic groups included non-Hispanic (NH) Black, Hispanic, and NH White and a binary (0/1) outcome defined subsequent depression in 2018. The total number of difficulties on the Nagi, Lawton, and Katz disability scales represented baseline (2016) functional disabilities with a secondary four-level (no/mild/severe with assistance/severe without assistance) disability indicator incorporated to examine the role of assistance with daily living., Results: Across age-groups, subsequent depression was significantly more prevalent among NH Whites with functional disabilities compared to counterparts reporting no disabilities. Compared to NH Black and Hispanic counterparts, midlife NH Whites were three times more likely to report subsequent depression with each unit increase in the functional disability score, after adjusting for covariates. However, we observed no such racial-ethnic differences among older adults. Among the 51+ severe with no assistance group, adjusted odds of subsequent depression among NH Whites was 2.5 times higher than minority counterparts., Conclusion: Health programs and environmental adaptations supporting functional care needs in later ages could be beneficial for improving mental health of adults with disabilities., Competing Interests: Declaration of competing interest The authors have no funding or conflicts of interest information to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Plant resource allocation strategies are thought to be largely a consequence of changing abiotic conditions and evolutionary history. However, biotic interactions also influence how a plant allocates resources. As a result, plants mediate indirect interactions between organisms above- and belowground through resource allocation. Neighboring plants can influence plant fitness directly through competition for resources, and indirectly by altering associated community interactions (associational effects), such as pollination, herbivory, and a suite of belowground interactions. Given the importance of community interactions for plant success, and the known ability for plant neighbors to change these interactions, the goal of this "pandemic project" was to understand how heterospecific plant neighbors alter plant resource allocation, whether this occurred through above- or belowground mechanisms, and whether this in turn alters biotic interactions and the relationship between a focal plant and its herbivore and soil community interactions. To do so, we established a common garden experiment, manipulating plant neighbor identity and the extent of interaction among neighbors (aboveground only, vs. above- and belowground interactions, using customized pot types), and measured changes to a focal plant and its biotic interactions over two growing seasons. We found evidence of both neighbor effects and pot type, showing that neighbor interactions affect a focal plant through both above- and belowground processes, and how the focal plant is affected depends on neighbor identity. Though neighbors did not directly alter herbivory or most soil microbial interactions, they did alter the relationship between belowground microbial communities and a plant response trait (specific leaf area). Plant resource allocation responses were reduced with time, showing the importance of extending experiments beyond a single growing season, and are an important consideration when making predictions about plant responses to changing conditions. This study contributes to a growing body of work showing how community contexts affect the above- and belowground interactions of a plant through plant resource allocation strategies., (© 2024 The Ecological Society of America.)

Background and Objectives: Fall incidents from unsafe home environments are frequent in older-adult homes but the literature is ambiguous whether it is the presence/absence, or the interplay of such conditions and physical functioning that is of salience. We therefore estimated whether unsafe home environment is adversely associated with subsequent falls among older adults and what proportion of this association was mediated through limitations in daily and instrumental activities of daily living (ADL/IADL)., Research Design and Methods: Using a nationally representative sample of community-dwelling Medicare beneficiaries (≥65 years) in the 2018-2019 National Health and Aging Trends Study (n = 2,599), we conducted bivariate and multivariable analyses. We examined baseline conditions of home disorders, unsafe bathroom settings, unsafe house/building features, and house disrepairs in 2018 and their relation with subsequent falls in 2019, after controlling for covariates. To assess whether ADL/IADL limitations mediated this relationship, we employed the Karlson-Holm-Breen methodology., Results: In 2019, the self-reported prevalence of falls among older adults was estimated at 34.68%. Although baseline home disorders had both a direct (adjusted odds ratio [aOR]: 1.14, 95% confidence interval [CI]:1.03,1.26) and an indirect effect through limitations in ADL and IADL (aOR: 1.01; 95% CI: 1.00,1.03), the relation between unsafe bathroom settings and subsequent falls was unclear. Unsafe house/building features and house disrepairs were not statistically significantly related either directly or indirectly with subsequent falls., Discussion and Implications: Addressing home disorders through policy and housing assessments to highlight home environmental safety would be essential to address falls among older adults., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The intent of this study was an evaluation of our effort to reduce the incidence of hypercalcemia in critically ill vitamin D-deficient patients with multiple traumatic injuries given cholecalciferol. Vitamin D deficiency was defined as a serum 25-hydroxy vitamin D concentration (25-OH vit D) of <20 ng/mL. Adult patients (>17 years of age) were given 10,000 IU of cholecalciferol daily with an intended target 25-OH vit D of >19.9 ng/mL. These patients were compared to a historical control group that underwent therapy with a higher target of >29.9 ng/mL. Patients received cholecalciferol via the feeding tube along with enteral nutrition (EN) until the target 25-OH vit D was achieved, EN discontinued, the nutrition support service signed off the patient, or the patient was discharged from the TICU. Patients were included if two consecutive weekly 25-OH vit D were measured. One hundred and three critically ill trauma patients were retrospectively studied. Fifty were given cholecalciferol therapy with the new lower target 25-OH vit D, and 53 were from a historical cohort aiming for the higher target. Hypercalcemia (serum ionized calcium concentration > 1.32 mmol/L) was reduced from 40% (21 out of 53 patients) to 4% (2 out of 50 patients; p < 0.001). None of the hypercalcemic patients were symptomatic. Readjustment of target 25-OH vit D concentration resulted in a ten-fold decrease in the rate of hypercalcemia and improved the safety of cholecalciferol therapy for critically ill patients with traumatic injuries.

A report published last year by the Centers for Medicare & Medicaid Services (CMS) highlighted that COVID-19 case counts are more likely to be high in lower quality nursing homes than in higher quality ones. Since then, multiple studies have examined this association with a handful also exploring the role of facility quality in explaining resident deaths from the virus. Despite this wide interest, no previous study has investigated how the relation between quality and COVID-19 mortality among nursing home residents may have changed, if at all, over the progression of the pandemic. This understanding is indeed lacking given that prior studies are either cross-sectional or are analyses limited to one specific state or region of the country. To address this gap, we analyzed changes in nursing home resident deaths across the US between June 1, 2020 and January 31, 2021 (n = 12,415 nursing homes X 8 months) using both descriptive and multivariable statistics. We merged publicly available data from multiple federal agencies with mortality rate (per 100,000 residents) as the outcome and CMS 5-star quality rating as the primary explanatory variable of interest. Covariates, based on the prior literature, consisted of both facility- and community-level characteristics. Findings from our secondary analysis provide robust evidence of the association between nursing home quality and resident deaths due to the virus diminishing over time. In connection, we discuss plausible reasons, especially duration of staff shortages, that over time might have played a critical role in driving the quality-mortality convergence across nursing homes in the US., Competing Interests: One of the study coauthors (SCT) is affiliated with the Fors MarshGroup (FMG), Arlington, VA. However, FMG did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Neither did FMG provide any financial support in the form of the coauthor’s salary and/or research materials. The coauthor affiliated with the FMG undertook work for this study in the role of an independent researcher working specifically and only during weekend hours outside of his employment with FMG. We also confirm that the study coauthor’s commercial affiliation with FMG does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Purpose: Previous studies indicate that the polymerase chain reaction (PCR) nasal assay for methicillin-resistant Staphylococcus aureus (MRSA) has a consistently high (>95%) negative predictive value (NPV) in ruling out MRSA pneumonia; however, optimal timing of PCR assay specimen and respiratory culture collection is unclear., Methods: A study including 736 patients from a community hospital system was conducted. Patients were included if they had undergone MRSA nasal screening with a PCR assay and had documented positive respiratory culture results., Results: In the full cohort, the MRSA PCR nasal screen assay was demonstrated to have an NPV of 94.9% (95% confidence interval [CI], 92.8%-96.5%) in ruling out MRSA-positive respiratory cultures. When evaluating the NPV by level of care (ie, where the MRSA PCR nasal assay sample was collected), no significant difference between values for samples collected in an intensive care unit vs medical/surgical units was identified (NPV [95%CI], 94.9% [92.7%-96.6%] vs 95.3% [88.4%-98.7%]). Additionally, NPV remained high with use of both invasive (NPV [95%CI], 96.8% [92.7%-99.0%]) and noninvasive (NPV [95%CI], 94.5% [91.7%-96.2%]) respiratory sampling methods. Finally, when evaluating the effect of time between MRSA PCR nasal screening and respiratory sample collection, we found high NPVs for all evaluated timeframes: within 24 hours, 93.8% (90.1%-96.4%); within 25 to 48 hours, 98.6% (92.7%-100.0%); within 49 hours to 7 days, 95.7% (91.4%-98.3%); within 8 to 14 days, 92.9% (85.1%-97.3%); and after more than 14 days, 95.5% (84.5%-99.4%)., Conclusion: We report high NPVs for up to 2 weeks between specimen collections, which allows clinicians to use a negative MRSA PCR nasal screen assay to rule out MRSA pneumonia, potentially leading to decreased exposure to MRSA-active antibiotics., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Current guidelines recommend that rapid systolic blood pressure (SBP) lowering to 140 mmHg may be considered in intracerebral hemorrhage (ICH) patients regardless of initial SBP. However, limited safety data exist in patients presenting with varying degrees of severe hypertension. The purpose of this study was to determine whether there was an increased risk of acute kidney injury (AKI) based upon degree of presentation hypertension in ICH patients whose blood pressure was reduced intensively., Methods: This retrospective, cohort study evaluated ICH patients treated with intensive blood pressure control (SBP ≤140 mmHg) who presented with three degrees of presentation hypertension: mild (SBP 141-179 mmHg), moderate (SBP 180-219 mmHg), and severe (SBP ≥ 220 mmHg). Univariate analysis of demographics variables, ICH severity, and factors known to impact AKI was conducted between the three groups. Post hoc testing was used to compare differences between specific groups, with a Bonferroni correction adjusting for multiple comparisons. Additionally, we conducted logistic regression analysis to determine whether baseline SBP group independently predicted AKI., Results: We included 401 patients (177 with mild, 124 with moderate, and 100 with severe hypertension). There was a significant increase in the prevalence of AKI between groups, with the severe group experiencing the highest rate (p < 0.001). The presence of severe hypertension was also found to independently predict AKI development (odds ratio 2.6; p < 0.001)., Conclusion: Our study observed higher rates of AKI in patients presenting with severe hypertension. Further research is needed to determine the most appropriate strategies for managing blood pressure in ICH patients presenting with higher SBP.

Background: Pediatric obesity prevalence remains at historically high levels. The objective of this study was to examine secular trends in the percentages of overweight/obese children who received notification from a health-care professional (HCP) about their unhealthy weight., Methods: We analyzed data of 25 570 (including 8639 overweight/obese) children aged 2-18 years collected from seven cross-sectional biennial surveys (National Health and Nutrition Examination Survey, 1999-2014), in which adolescents (16 years and older) and caregivers, mostly biological mothers, of children (2-15 years) were asked 'Has a doctor or other health professional ever told you that you (or your child) were overweight?', Results: Approximately 90% of overweight/obese children visited HCPs at least once in the past 12 months, but only 22.12% (s.e.=1.92) in 1999 to 34.43% (2.35) in 2014 of the overweight/obese children were notified by HCPs about unhealthy weight. The biennial increase in odds of receipt of notification of unhealthy weight was 1.08 (95% confidence interval=(1.04-1.12)). Greater likelihood for receipt of notification was associated with being obese (odds ratio=5.03 (4.29-5.89) vs overweight); black (1.24 (1.06-1.46)) or Hispanic race/ethnicity (1.72 (1.45-2.04) vs white); female sex (1.22 (1.07-1.11) vs boys); and child's insurance status (1.31 (1.08-1.59) vs uninsured). There were increasing odds of being notified with increasing age: 1.00 (reference), 2.24 (2.06-2.62), 3.22 (2.50-4.13) and 4.87 (3.76-6.32) for children 2-5, 6-11, 12-16 and 16+ year old, respectively. The frequency of medical contact was linearly associated with an increased likelihood of being notified., Conclusions: Notification of child's unhealthy weight by HCPs increased significantly between 1999 and 2014, but the opportunity of clinical intervention remained substantially under-utilized.

The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity/anticonvulsant effects). Calculated TIs for A-1295120, CMPPE, rac-BHFF, GS39783, and A-1474713 were 5.31x, 5.00x, 4.74x, 3.41x, and 1.83x, respectively, whereas baclofen was <1. The results presented here suggest the DBA/2J mouse AGS test is a potentially useful screening model for detecting PD effects of GABA(B) PAMs and can provide an initial read-out on target-related motor side-effects. Furthermore, an improved TI was observed for PAMs compared to baclofen, indicating the PAM approach may be a viable therapeutic alternative to baclofen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.

Background: We see a growing number of older adults receiving long-term care in industrialized countries. The Healthcare Utilization Model by Andersen suggests that individual need characteristics influence utilization. The purpose of this study is to analyze correlations between need characteristics and service utilization in home care arrangements., Methods: 1,152 respondents answered the questionnaire regarding their integration of services in their current and future care arrangements. Care recipients with high long-term care needs answered the questionnaire on their own, the family caregiver assisted the care recipient in answering the questions, or the family caregiver responded to the questionnaire on behalf of the care recipient. They were asked to rank specific needs according to their situation. We used descriptive statistics and regression analysis., Results: Respondents are widely informed about services. Nursing services and counseling are the most used services. Short-term care and guidance and training have a high potential for future use. Day care, self-help groups, and mobile services were the most frequently rejected services in our survey. Women use more services than men and with rising age utilization increases. Long waiting times and bad health of the primary caregiver increases the chance of integrating services into the home care arrangements., Conclusion: The primary family caregiver has a high impact on service utilization. This indicates that the whole family should be approached when offering services. Professionals should react upon the specific needs of care dependents and their families.

Objective: To evaluate the processes by which pharmaceuticals are added to the formularies of Australian paediatric hospitals., Design: Descriptive study of the processes and outcomes of all submissions to Australian paediatric hospital drug and therapeutics committees from 1 July 2010 to 31 December 2011., Setting: All eight tertiary paediatric hospitals in Australia., Participants: Interviews with committee secretaries or delegates and document analysis., Main Outcome Measures: Total number of formulary applications, stratified by therapeutic class, approval rates for each hospital and quality of supporting information., Results: One hundred and twenty applications were considered during the study period, with most applications approved (range, 67%-100%). Neurological agents were the most common therapeutic class considered. A conflict of interest was declared for 10 applications (8%). Forty-five (38%) were independently reviewed by a statewide medicines advisory committee or hospital pharmacist. Several committees approved identical applications during the period of review and with different outcomes. For applications submitted for new drugs or new indications (95 applications), supporting data included randomised controlled trials (37/95), case series (36/95), product information (34/95) and narrative reviews (29/95). Few applications (14/95) included a systematic review or meta-analysis. No application included an evaluation of the risk of bias of supporting studies., Conclusions: There is limited high-quality evidence informing paediatric hospital-based drug approvals. Approval processes vary considerably among institutions with substantial duplication of effort and variable outcomes. Resources and training appear insufficient given the technical complexity of submissions. A national, standardised approach to hospital-based drug evaluation could reduce overlap and improve decision making.

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A straightforward approach to novel (5-nitropyridin-2-yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamate building blocks is presented in this study. Their construction is achieved by condensation of N-carbamate alpha- and beta-amino carbonyl derivatives with 1-methyl-3,5-dinitro-2-pyridone 1 under microwave irradiation. Judiciously chosen modifications in the nature of the parent carbonyl starting material has influenced the regiochemical outcome of the reaction and allowed an efficient access to novel nitrogen-containing scaffolds. Compounds sharing morphological similarities have been gathered in three libraries differing from each other in a single structural parameter.

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.

SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.

Background and Purpose: The large-conductance Ca(2+)-activated K(+) channel (BK(Ca), K(Ca)1.1) links membrane excitability with intracellular Ca(2+) signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK(Ca) channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651)., Experimental Approach: (86)Rb(+) efflux in HEK-293 cells expressing BK(Ca) was measured. Effects of A-272651 on BK(Ca) alpha- and BK(Ca) alphabeta1-mediated currents were evaluated by patch-clamp. Effects on contractility were assessed using low-frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A-272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG)., Key Results: A-272651 (10 microM) inhibited (86)Rb(+) efflux evoked by NS-1608 in HEK-293 cells expressing BK(Ca) currents. A-272651 concentration-dependently inhibited BK(Ca) currents with IC(50) values of 4.59 microM (Hill coefficient 1.04, measured at +40 mV), and 2.82 microM (Hill coefficient 0.89), respectively, for BK(Ca) alpha and BK(Ca) alphabeta1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC(50) values of 4.05+/-0.05 and 37.95+/-0.12 microM, respectively. In capsaicin-sensitive DRG neurons, application of A-272651 increased action potential firing and prolonged action potential duration., Conclusions and Implications: These data demonstrate that A-272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BK(Ca) blockers, A-272651 represents one of the first small molecule BK(Ca) channel blockers that could serve as a useful tool for further characterization of BK(Ca) channels in physiological and pathological states.

Background: Provision of cardiac rehabilitation is inadequate in all countries in which it has been measured. This study assesses the provision in the United Kingdom and the changes between 1998 and 2004., Methods: All UK cardiac rehabilitation programmes were surveyed annually. Figures for each year were up-rated to account for missing data and compared with national data for acute myocardial infarction, coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). The total numbers and percentage of eligible patients included were charted for 7 years., Results: For centres giving figures, the total number treated rose from 29,890 in 1998 to 37,129 in 2004. The up-rated figures show that the percentage of eligible patients enrolled rose from 25.0% in 1998 to 31.5% in 1999 and has changed little since, falling from 31.3% in 2002 to 28.5% in 2004. About 25% of myocardial infarction patients, 75% of CABG patients and 20% of PCI patients joined cardiac rehabilitation programmes., Conclusions: The National Service Framework for Coronary Heart Disease set a target for 85% of myocardial infarct and coronary revascularization patients to be enrolled in rehabilitation programmes. Only one-third of this number is currently being enrolled and the percentage is falling.

Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.

Background: The coronary heart disease (CHD) National Service Framework (NSF) sets standards and milestones. For acute myocardial infarction (AMI) or coronary revascularization, 'Milestone 3, of Standard 12 requires that, by April 2002, every hospital should have clinical audit data no more than 12 months old showing 'total number and % of those recruited to cardiac rehabilitation who, one year after discharge, report: regular physical activity of at least 30 minutes duration on average five times a week, not smoking and a Body Mass Index (BMI) of <30 kg/m2'. This study looked at cost, method and practicalities of retrieving this data., Methods: A postal questionnaire was used to follow-up coronary patients who started our cardiac rehabilitation programme between 1 April 2001 and 31 March 2004. The project was costed., Results: Three hundred and seventy-five (33 per cent) AMI patients, 412 (36 per cent) coronary artery bypass grafting (CABG) patients and 343 (30 per cent) percutaneous coronary intervention (PCI) patients entered the cardiac rehabilitation programme over 3 years. Completed questionnaires were received from 903 (80 per cent). Post-AMI patients or those stratified as high risk for further cardiac events were least likely to respond. Of responders, 74 per cent were exercising regularly, 95 per cent were not smoking and 79 per cent had a BMI <30 kg/m2., Conclusion: Targets for smoking and BMI set by the NSF are too low and were achieved by most patients before the start of cardiac rehabilitation. Patients who are post-AMI or are stratified as high risk need to be targeted if a high level of follow-up is to be achieved.

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels. 2. A-151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide-sensitive whole-cell current and fluorescence-based membrane potential responses (-log EC(50)=7.63) in guinea-pig bladder smooth muscle cells. 3. Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4-dihydropyridine opener [(125)I]A-312110. A-151892 displaced [(125)I]A-312110 binding to bladder membranes with a -log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites. 4. In pig bladder strips, A-151892 suppressed phasic, carbachol-evoked and electrical field stimulus-evoked contractility in a glibenclamide-reversible manner with -log IC(50) values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (-log IC(50)=7.81) and portal vein (-log IC(50)=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle. 5. In vivo, A-151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED(35%) values of 8.05 and 7.43, respectively. 6. These results demonstrate that naphthylamide analogs exemplified by A-151892 are novel K(ATP) channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms.

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.

Psychological and quality of life measures are important in the assessment of cardiac rehabilitation (CR) patients and the outcome of treatment. This study aimed to assess the utility and sensitivity to change of three simple questionnaires in a CR setting. A total of 1403 patients who entered CR over 51 months were studied. Patients completed questionnaires before and after their phase 3 CR program-Hospital Anxiety and Depression (HAD) scale, WONCA/COOP charts and an analogue score of wellbeing. The three instruments took about 5.5 min in total to complete and 30 s to interpret. There were highly significant reductions in mean anxiety score-from 6.04 to 4.67 (P<0.001, 95% CI -1.52 to -1.16) and depression from 4.00 to 2.52 (P<0.001, 95% CI -1.62 to -1.29) The mean analogue of wellbeing score improved from 7.09 to 8.19 (P<0.001, 95% CI 0.97-1.22 ) There were highly significant improvements in five of the six WONCA domains. There were significant correlations between improvements in scores from all instruments. The sensitivity indices were in the 'good' range for changes in WONCA physical fitness domain and subjective well-being score and in the (moderate) range for changes in depression, well-being and WONCA overall health. Initial physical fitness was significantly correlated with the initial levels of all psychometric scores except anxiety and WONCA feelings, but improvements in fitness were not correlated with any changes in psychometric scores. The instruments described were quick to administer and to interpret and showed sensitivities to change superior to those which have been reported for other questionnaires. We believe them to be practical tools for use in CR units.

The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H(3) receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H(3) receptor were discovered.

2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent.

We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips. Additionally, A-151892 was found to selectively inhibit unstable bladder contractions in vivo in an obstructed rat model of myogenic bladder function

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.

During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56(bright) and CD56(dim)). In this report, it is shown that CD56(bright) NK cells produce significantly greater levels of interferon-gamma, tumor necrosis factor-beta, granulocyte macrophage-colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56(dim) NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56(bright) NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine production by CD56(bright) NK cells. It is proposed that human CD56(bright) NK cells have a unique functional role in the innate immune response as the primary source of NK cell-derived immunoregulatory cytokines, regulated in part by differential monokine production.

Objective: To compare the cost of using intravenous epoprostenol with that of inhaled nitric oxide (NO) for treating episodes of pulmonary hypertension in children with congenital heart disease., Design: An analysis of the cost of epoprostenol and NO use over the previous 18 months was performed. Three 6-month periods were identified, two in which epoprostenol was used and the third in which inhaled NO was introduced for the treatment of pulmonary hypertension., Setting: A 10-bed pediatric cardiac intensive care unit, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England., Subjects: Children with congenital heart disease and persistently elevated pulmonary artery pressure following cardiac surgery., Main Outcome Measures: The total duration of use of epoprostenol and inhaled NO was documented. The costs per hour for epoprostenol and inhaled NO were calculated and the annual cost of each agent was estimated., Results: In the two 6-month periods prior to the introduction of inhaled NO, epoprostenol was used on 14 occasions (5 in the first period, 3 in the second). In the last 6-month period, nine children required pulmonary vasodilator therapy on 14 occasions. All nine children were treated successfully with inhaled NO; none were given or needed epoprostenol, as NO always was effective in providing pulmonary vasodilatation. For resistant pulmonary hypertension, increasing the concentration of NO would have been the next therapeutic option. The cost for the two 6-month periods using epoprostenol was $19,483.48 for the drug and $283.25 for equipment costs (total cost $19,766.73). There was no expenditure on epoprostenol in the final 6-month period. The cost of NO was $465. However, the total expenditure, including the delivery and monitoring system, was $4,722.85., Conclusions: Using inhaled NO in our pediatric cardiac intensive care unit abolished the use of epoprostenol during the reported monitoring period. The cost savings were significant, amounting to 12% of the annual drug budget for the unit. The cost of setting up the inhaled NO delivery system is recouped rapidly. The ease of delivery and measurement of inhaled NO also may have contributed to its increased clinical use.

The production of hydrogen from substrates and substrate mixture of sugar alcohols and Polydextrose was determined, both in vivo using the breath hydrogen test, and in vitro, using human faecal microorganisms in anaerobic culture. One objective was to test a previous assumption that the stoichiometry of hydrogen production from different alternative carbohydrates is similar. Another objective was to discover whether hydrogen responses from mixtures of substrates were simply additive, or whether interactions occurred. The breath tests were performed in a 10 subject x 10 substrate factorial design with substrates and substrate mixtures (5-11 g) administered in 42 g chocolate confectionery. Incorporation of the alternative carbohydrates lactitol (L), Isomalt (I) and Polydextrose (P) into otherwise conventional confectionery increased breath hydrogen production by approximately 112, 73 and 11%/g respectively. There was no interaction between L and I or between P and I, but a combination of L and P approximately doubled the breath hydrogen anticipated from their individual contributions (P < 0.05). Anaerobic cultures showed a sixfold range in the efficiency of converting individual substrates and mixtures to hydrogen gas (0.003-0.018 kJ H2 per kJ carbohydrate). The positive interaction between L and P, and the lack of interaction between L and I, and between P and I, found in vivo were reproduced in vitro. The work showed that interpretation of the hydrogen breath test is confounded by differing stoichiometries for hydrogen production, by interaction between substrates and by an uncertain extent to which small intestinal hydrolysis yielding species with a fermentation stoichiometry that differs from the parent substrate.

Data from feeder cattle teleauction sales in Georgia from 1977 to 1988 were analyzed using least squares analysis of variance to detect significant (P less than .05) influential factors on price. The sample was divided into two periods, 1977 to 1982 and 1983 to 1988, to test whether the influence of factors had changed over the time periods. The test of equality was rejected (P less than .01) using a Chow test, thus suggesting a change had occurred. Hereford breeds were discounted in the latter period whereas Angus breeds generated a premium in the earlier period. Treatment for specific diseases resulted in premium prices, as did preconditioning, during the 1983 to 1988 period. The effect of seasonality on prices decreased over the two time periods. The optimal lot size increased from 228 to 280 cattle during the time periods.

Over a five-year period, 162 patients with coronary disease joined a physical rehabilitation course at a community sports centre gymnasium under the supervision of a general practitioner. One hundred and forty-seven patients had suffered a recent or old myocardial infarction and 15 suffered from angina pectoris. One hundred and thirty-eight patients (85 per cent) completed a three-month course of exercises, 16 (10 per cent) defaulted and eight (5 per cent) were withdrawn. One patient died at home during the three-month course. There were no changes in weight, blood pressure or blood fat measurements during the course but predicted maximum oxygen uptake increased by 26.9 per cent and the double product after effort (which is proportional to myocardial oxygen uptake) decreased by 13.6 per cent.We believe that the rehabilitation of patients in community sports centres is safe and effective and should be more widely practised.

Prescribing patterns and blood pressure control have been studied in 1101 patients treated at three specialist hypertension clinics in Britain. Seventy-four per cent of the patients were already receiving treatment at the time they were referred by their general practitioners. Though the initial improvement in blood pressure control was satisfactory, there was often some deterioration of control over the long term. The pressure exceeded 140/90 mmHg in the majority of patients followed for a year or more. During 1971-5 diuretics remained first preference, with increasing use of beta-blockers and a distinct decline in the use of sympathetic neurone blockers both by hospital staff and referring practitioners. Multiple drug treatment was common, nearly half the patients requiring more than one antihypertensive drug. In newly treated patients the frequency of cessation of a particular class of drug because of side effects or lack of efficacy ranged from 6 per cent with diuretics to 57 per cent with adrenergic neurone blocking drugs. Long-term blood pressure control still presents many problems, and the results contrast with the more optimistic interpretations sometimes placed on short-term clinical trials of antihypertensive effect.

A computer-based medical record system has been developed to help with research into hypertension and the management of patients with hypertension. Standard medical records are replaced by data collection forms and case notes printed by the computer. A computer-generated document for recording information at follow-up visits contains an up-to-date summary of the important clinical features with warnings of risk factors. A blood-pressure graph and a letter for the general practitioner are produced on request. The system has been used in three clinics for two years and is being tested in general practice. Information on 900 newly-referred patients has been recorded and at present data on 30 to 40 new patients and 160 follow-up visits are added each month.

The initial record of history and clinical findings has been studied in 278 patients attending three hypertension clinics. Half of these were randomly allocated to standard case notes and the other half to a special structured questionnaire record. The investigations carried out in a total of 521 patients with raised arterial pressures were examined. The records derived from the structured questionnaire were much more complete than the standard case notes but the difference was less obvious for a positive record than a negative one. None of the investigations was carried out in all patients, even though it was the policy of the clinics that most of them should be. A possible aetiological diagnosis was made in 28 patients and, at the time of writing, 3 patients had benefited from a surgical operation carried out as a result of investigation. These results raise the question of the quality of the initial care of hypertensive patients and suggest that the structured questionnaires might lead to an improvement. It remains to be established whether all the information collected does influence the outcome in patients with hypertension.

A total of 278 hypertensive patients in three clinics were randomly allocated to have their medical records held in a computer system (136) or on standard hospital notes (142). For the computer system the doctor completed a structured input form, and the information on symptoms, physical findings, and diagnoses was more complete than that in the standard notes. This resulted in certain symptoms and risk factors being recognised more often when the computer system was used. The hypertension clinics' routines were not disrupted by the introduction of a computer-held system, and follow-up consultation times were not affected by the type of records kept, although the first consultation took eight minutes longer when computer documents were completed. The patients remained in the trial for one year and clinical management was assessed from blood pressure control, drop-out rates, and the frequency of performing investigations. These estimates of management showed no significant difference between the two groups, but the attempt to tailor the computer system to help management made the system acceptable to the doctors using it. The computer system continues to be used and is providing data for research into hypertension.

Nine male subjects performed continuous incremental exercise on a bicycle ergometer pedaling at 50 and 90 rpm in a normal glycogen state (NG) and at 50 rpm in a glycogen-depleted state (GD) to determine if alterations in pedaling frequency and muscle glycogen content would affect their "anaerobic thresholds." Ventilatory [T(vent)] and lactate [T(lac)] thresholds were identified as the points after which expired minute volume and blood lactate began to increase nonlinearly as a function of work rate. The GD protocol elicited a significant divergence between the two thresholds shifting the T(vent) to a lesser and the T(lac) to a greater work rate relative to the NG state. When the pedaling frequency was increased to 90 rpm in the NG condition, the T(lac) was shifted to a lesser work rate relative to the 50-rpm NG condition. A correlation of only 0.71 was obtained between subjects' T(vent) and T(lac). In subjects of less than 70 kg body wt, the T(lac) came at a work rate 400 kg.m.min-1 less than in subjects of greater than 80 kg body wt despite equivalent O2 uptake. The observation that the T(vent) and T(lac) could be manipulated independently of each other reveals limitations in using the T(vent) to estimate the so-called anaerobic threshold.