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Rationale: Many physicians are reluctant to discuss a patient's prognosis when there is significant prognostic uncertainty.Objectives: We sought to understand surrogate decision makers' views regarding whether physicians should discuss prognosis in the face of uncertainty.Methods: We conducted semi-structured interviews with 179 surrogates for 142 incapacitated patients at high risk of death in four intensive care units at an academic medical center. The interviews explored surrogates' attitudes about whether physicians should discuss prognosis when they cannot be certain their prognostic estimates are correct. We used constant comparative methods to analyze the transcripts. Validation methods included triangulation by multidisciplinary analysis and member checking.Measurements and Main Results: Eighty-seven percent (155/179) of surrogates wanted physicians to discuss an uncertain prognosis. We identified five main reasons for this, including surrogates' belief that prognostic uncertainty is unavoidable, that physicians are their only source for prognostic information, and that discussing prognostic uncertainty leaves room for realistic hope, increases surrogates' trust in the physician, and signals a need to prepare for possible bereavement. Twelve percent (22/179) of surrogates felt that discussions about an uncertain prognosis should be avoided. The main explanation was that it is not worth the potential emotional distress if the prognostications are incorrect. Surrogates suggested that physicians should explicitly discuss uncertainty when prognosticating.Conclusions: The majority of surrogates of patients that are critically ill want physicians to disclose their prognostic estimates even if they cannot be certain they are correct. This stems from surrogates' belief that prognostic uncertainty is simultaneously unavoidable and acceptable. [ABSTRACT FROM AUTHOR]

This paper investigates the use of shoulder supports with stroke patients in Canada and compares the results of two survey questionnaires carried out in 1984 and 1994. It describes which shoulder supports therapists are using with stroke patients and which goals they hope to achieve with specific supports. The Lopboard, Cuff Type Sling, and Arm Trough Support were the most frequently used supports at both time periods. The most frequent goal chosen for each of these three most frequently chosen supports was the same at both time periods but were chosen significantly less frequently in 1994. There was a significant decrease in the use of the Bobath Axial Roll over the ten year period. This follow up questionnaire documents the limited changes which have occurred in the last ten years in the management of the shoulder following stroke, raises some questions about this area of practice, and outlines some solutions including the need to base occupational therapy practice on more evidence. [ABSTRACT FROM AUTHOR]

Samarium diiodide (SmI 2 ) exhibits high selectivity for N 2 R catalyzed by molybdenum complexes; however, it has so far been employed only as a stoichiometric reagent (0.3 equiv of NH 3 per Sm) combined with coordinating proton sources (e.g., H 2 O, ROH). The latter inhibit catalytic turnover of Sm III owing to buildup of stable hydroxide/alkoxide sinks. Here, we report a tandem Sm/Mo-catalyzed e N 2 R system that achieves the lowest overpotential and highest Faradaic efficiency (82%) reported to date for nonaqueous e N 2 R at ambient pressure. Up to 8.4 equiv of NH 3 is produced per Sm, representing a 25-fold increase over N 2 R with stoichiometric SmI 2 . A noncoordinating proton source enables electrochemical SmI 3 /SmI 2 cycling at the applied potential of -1.45 V vs Fc +/0 .

Undergraduate research has been identified as a high-impact educational practice. However, despite the body of evidence on the outcomes of undergraduate research, few studies have focused on the influences students face regarding participation. Developed using Science Capital and Social Cognitive Career Theory, a survey comprised of potential influences to undergraduate science research participation was disseminated to science majors at four R1 institutions in the Southeastern United States. Participation rates across several demographic factors and effect of participation influences were analysed. Results reveal a significantly greater proportion of the Lesbian, Gay, Bisexual, Transgender, Queer, Plus (LGBTQ+) and disability communities indicating participating in research than their peers. Additionally, fourteen participation influences were identified as having a significant difference in their level of influence to the ability to participate in research between researchers and non-researchers. These include professor influence, interest in research, interest in science, coursework in the major, and major all being rated as opportunities with a significant difference of effect between researchers and those who have not yet participated in research. The results of this study will be beneficial for science departments and their respective institutions to improve the equity of access to their undergraduate research experiences., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Boyd, Lazar. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The selectivity of SmI 2 as a one electron-reductant motivates the development of methods for reductive Sm-catalysis. Photochemical methods for SmI 2 regeneration are desired for catalytic transformations. In particular, returning Sm III -alkoxides to Sm II is a crucial step for Sm-turnover in many potential applications. To this end, photochemical conditions for reduction of both SmI 3 and a model Sm III -alkoxide to SmI 2 (THF) n are described here. The Hantzsch ester can serve either as a direct photoreductant or as the reductive quencher for an Ir-based photoredox catalyst. In contrast to previous Sm III reduction methodologies, no Lewis acidic additives or byproducts are involved, facilitating selective ligand coordination to Sm. Accordingly, Sm II species can be generated photochemically from SmI 3 in the presence of protic, chiral, and/or Lewis basic additives. Both the photoreductant and photoredox methods for SmI 2 generation translate to intermolecular ketone-acrylate coupling as a proof-of-concept demonstration of a photodriven, Sm-catalyzed reductive cross-coupling reaction.

Samarium diiodide (SmI 2 ) is a privileged, single-electron reductant deployed in diverse synthetic settings. However, generalizable methods for catalytic turnover remain elusive because of the well-known challenge associated with cleaving strong Sm III -O bonds. Prior efforts have focused on the use of highly reactive oxophiles to enable catalyst turnover. However, such approaches give rise to complex catalyst speciation and intrinsically limit the synthetic scope. Herein, we leveraged a mild and selective protonolysis strategy to achieve samarium-catalyzed, intermolecular reductive cross-coupling of ketones and acrylates with broad scope. The modularity of our approach allows rational control of selectivity based on solvent, p K a (where K a is the acid dissociation constant), and the samarium coordination sphere and provides a basis for future developments in catalytic and electrocatalytic lanthanide chemistry.

Controlling product selectivity in multiproton, multielectron reductions of unsaturated small molecules is of fundamental interest in catalysis. For the N 2 reduction reaction (N 2 RR) in particular, parameters that dictate selectivity for either the 6H + /6e - product ammonia (NH 3 ) or the 4H + /4e - product hydrazine (N 2 H 4 ) are poorly understood. To probe this issue, we have developed conditions to invert the selectivity of a tris(phosphino)borane iron catalyst ( Fe ), with which NH 3 is typically the major product of N 2 R, to instead favor N 2 H 4 as the sole observed fixed-N product (>99:1). This dramatic shift is achieved by replacing moderate reductants and strong acids with a very strongly reducing but weakly acidic Sm II -(2-pyrrolidone) core supported by a hexadentate dianionic macrocyclic ligand ( Sm II -PH) as the net hydrogen-atom donor. The activity and efficiency of the catalyst with this reagent remain high (up to 69 equiv of N 2 H 4 per Fe and 67% fixed-N yield per H + ). However, by generating N 2 H 4 as the kinetic product, the overpotential of this Sm-driven reaction is 700 mV lower than that of the mildest reported set of NH 3 -selective conditions with Fe . Mechanistic data support assignment of iron hydrazido(2-) species FeNNH 2 as selectivity-determining: we infer that protonation of FeNNH 2 at N β , favored by strong acids, releases NH 3 , whereas one-electron reduction to FeNNH 2 - , favored by strong reductants such as Sm II -PH, produces N 2 H 4 via reactivity initiated at N α . Spectroscopic data also implicate a role for Sm III -binding to anionic Fe N 2 - (via an Fe -N 2 - - Sm III species) with respect to catalytic efficacy.

Coordination of alcohols to the single-electron reductant samarium diiodide (SmI 2 ) results in substantial O-H bond weakening, affording potent proton-coupled electron transfer (PCET) reagents. However, poorly defined speciation of SmI 2 in tetrahydrofuran (THF)/alcohol mixtures limits reliable thermodynamic analyses of such systems. Rigorous determination of bond dissociation free energy (BDFE) values in such Sm systems, important to evaluating their reactivity profiles, motivates studies of model Sm systems where contributing factors can be teased apart. Here, a bulky and strongly chelating macrocyclic ligand (( t Bu2 ArOH) 2 Me 2 cyclam) maintains solubility, eliminates dimerization pathways, and facilitates clean electrochemical behavior in a well-defined functional model for the PCET reactivity of Sm II with coordinating proton sources. Direct measurement of thermodynamic parameters enables reliable experimental estimation of the BDFEs in 2-pyrrolidone and MeOH complexes of (( t Bu2 ArO) 2 Me 2 cyclam)Sm II , thereby revealing exceptionally weak N-H and O-H BDFEs of 27.2 and <24.1 kcal mol -1 , respectively. Expanded thermochemical cycles reveal that this bond weakening stems from the very strongly reducing Sm II center and the formation of strong Sm III -alkoxide (and -pyrrolidonate) interactions in the PCET products. We provide a detailed analysis comparing these BDFE values with those that have been put forward for SmI 2 in THF in the presence of related proton donors. We suggest that BDFE values for the latter systems may in fact be appreciably higher than the system described herein. Finally, protonation and electrochemical reduction steps necessary for the regeneration of the PCET donors from Sm III -alkoxides are demonstrated, pointing to future strategies aimed at achieving (electro)catalytic turnover using Sm II -based PCET reagents.

Inspired by momentum in applications of reductive photoredox catalysis to organic synthesis, photodriven transfer hydrogenations toward deep (>2 e - ) reductions of small molecules are attractive compared to using harsh chemical reagents. Noteworthy in this context is the nitrogen reduction reaction (N 2 RR), where a synthetic photocatalyst system had yet to be developed. Noting that a reduced Hantzsch ester (HEH 2 ) and related organic structures can behave as 2 e - /2 H + photoreductants, we show here that, when partnered with a suitable catalyst (Mo) under blue light irradiation, HEH 2 facilitates delivery of successive H 2 equivalents for the 6 e - /6 H + catalytic reduction of N 2 to NH 3 ; this catalysis is enhanced by addition of a photoredox catalyst (Ir). Reductions of additional substrates (nitrate and acetylene) are also described.

Half-sandwich rhodium monohydrides are often proposed as intermediates in catalysis, but little is known regarding the redox-induced reactivity accessible to these species. Herein, the bis(diphenylphosphino)ferrocene (dppf) ligand has been used to explore the reactivity that can be induced when a [Cp*Rh] monohydride undergoes remote (dppf-centered) oxidation by 1e - . Chemical and electrochemical studies show that one-electron redox chemistry is accessible to Cp*Rh(dppf), including a unique quasi-reversible Rh II/I process at -0.96 V vs. ferrocenium/ferrocene (Fc +/0 ). This redox manifold was confirmed by isolation of an uncommon Rh II species, [Cp*Rh(dppf)] + , that was characterized by electron paramagnetic resonance (EPR) spectroscopy. Protonation of Cp*Rh(dppf) with anilinium triflate yielded an isolable and inert monohydride, [Cp*Rh(dppf)H] + , and this species was found to undergo a quasireversible electrochemical oxidation at +0.41 V vs. Fc +/0 that corresponds to iron-centered oxidation in the dppf backbone. Thermochemical analysis predicts that this dppf-centered oxidation drives a dramatic increase in acidity of the Rh-H moiety by 23 pK a units, a reactivity pattern confirmed by in situ 1 H NMR studies. Taken together, these results show that remote oxidation can effectively induce M-H activation and suggest that ligand-centered redox activity could be an attractive feature for the design of new systems relying on hydride intermediates., (© 2022 Wiley-VCH GmbH.)

The mealybug, Planococcus ficus (Signoret), is a primary vineyard pest in California and other grape-growing regions throughout the World. Mating disruption programs are commercially available to manage Pl. ficus, but widespread adoption has been limited, in part, by high costs compared with insecticide programs. To improve mating disruption economic effectiveness, different deployment technologies (passive, aerosol, and microencapsulated formulations) were individually examined. Adult male Pl. ficus captures in pheromone traps and categorical ratings of vine infestation or crop damage suggest that all deployment strategies lowered mealybug densities or damage. Using passive dispensers, deployment rates of 310 and 465 per ha lowered Pl. ficus crop damage similar to 615 per ha, a rate commonly used in commercial operations; reduced rates would lower product and deployment costs. Meso dispensers, containing more a.i., deployed at 35 per ha did not have a treatment impact, but a microencapsulated formulation and aerosol canisters lowered male flight captures and/or crop damage. Male mealybug flight activity was greatest from 0500-1100 hr, which coincided with temperatures >16° and <32°C. These restricted times and temperatures suggest programable dispensers might allow pheromone deployment to coincide only with flight patterns. A large field trial using passive dispensers found greater treatment separation after 3 yr of pheromone deployment. Discrepancies in results among vineyards may be related to Pl. ficus density, but combined results from all trials suggest that different deployment technologies can be used to impact Pl. ficus densities and damage, even at reduced rates, especially with continued use over multiple seasons., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.)

Parad items used in Hindu practices and Ayurvedic medicines contain elemental mercury (Hg0) and have traditionally been used in prayer and to treat a variety of diseases including diabetes, heart conditions, and sexual dysfunction. These items are often referred to as amalgams of silver, and take the form of shivlings, statues of gods, necklaces, and other jewelry. Fourteen parad items were purchased from online vendors in India and the United States and analyzed. All items produced copious amounts of Hg0 vapor, with Hg0 concentrations exceeding 1,000,000 ng/m3 as measured using a Mercury Instruments Mercury Tracker 3000 IP atomic absorption spectrometer. Measured concentrations were highly variable, so a simple qualitative experiment employing a UV-C light source and a thin-layer chromatography plate impregnated with a fluorescent dye that glows green when irradiated at 254 nm allowed for the indirect visualization of the Hg0 being evolved. In addition, all items were screened using a hand-held X-ray fluorescence analyzer to estimate the concentration of Hg, Sn, Pb, As, and Cd on the surface of the item. Select samples were then digested in aqua regia and analyzed for Hg content using a direct mercury analyzer. All samples were found to exceed 20% by mass Hg. The digestates were analyzed using inductively-coupled plasma-optical emission spectrometry and were determined to be between 10-55% by mass Pb and contain up to 0.3% by mass As. While Article 4 of the Minamata Convention on Mercury specifically requires parties to stop importing, exporting, and manufacturing Hg-added products, products used in traditional and religious practices are excluded., Competing Interests: M.W.H. is employed by Olympus Corporation of the Americas. The funder provided support in the form of salaries for authors [M.W.H.], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Monomeric half-sandwich rhodium hydride complexes are often proposed as intermediates in catalytic cycles, but relatively few such compounds have been isolated and studied, limiting understanding of their properties. Here, we report preparation and isolation of a monomeric rhodium(III) hydride complex bearing the pentamethylcyclopentadienyl (Cp*) and bis(diphenylphosphino)benzene (dppb) ligands. The hydride complex is formed rapidly upon addition of weak acid to a reduced precursor complex, Cp*Rh(dppb). Single-crystal X-ray diffraction data for the [Cp*Rh] hydride, which were previously unavailable for this class of compounds, provide evidence of the direct Rh-H interaction. Complementary infrared spectra show the Rh-H stretching frequency at 1986 cm -1 . In contrast to results with other [Cp*Rh] complexes bearing diimine ligands, treatment of the isolated hydride with strong acid does not result in H 2 evolution. Electrochemical studies reveal that the hydride complex can be reduced only at very negative potentials (ca. -2.5 V vs ferrocenium/ferrocene), resulting in Rh-H bond cleavage and H 2 generation. These results are discussed in the context of catalytic H 2 generation, and development of design rules for improved catalysts bearing the [Cp*] ligand.

United States-based biorepositories are on the cusp of substantial change in regulatory oversight at the same time that they are increasingly including samples and data from large populations, e.g. all patients in healthcare system. It is appropriate to engage stakeholders from these populations in new governance arrangements. We sought to describe community recommendations for biorepository governance and oversight using deliberative community engagement (DCE), a qualitative research method designed to elicit lay perspectives on complex technical issues. We asked for stakeholders to provide input on governance of large biorepositories at the University of California (UC), a public university. We defined state residents as stakeholders and recruited residents from two large metropolitan areas, Los Angeles (LA) and San Francisco (SF). In LA, we recruited English and Spanish speakers; in SF the DCE was conducted in English only. We recruited individuals who had completed the 2009 California Health Interview Survey and were willing to be re-contacted for future studies. Using stratified random sampling (by age, education, race/ethnicity), we contacted 162 potential deliberants of whom 53 agreed to participate and 51 completed the 4-day DCE in June (LA) and September-October (SF), 2013. Each DCE included discussion among deliberants facilitated by a trained staff and simultaneously-translated in LA. Deliberants also received a briefing book describing biorepository operations and regulation. During the final day of the DCE, deliberants voted on governance and oversight recommendations using an audience response system. This paper describes 23 recommendations (of 57 total) that address issues including: educating the public, sharing samples broadly, monitoring researcher behavior, using informative consent procedures, and involving community members in a transparent process of biobank governance. This project demonstrates the feasibility of obtaining meaningful input on biorepository governance from diverse lay stakeholders. Such input should be considered as research institutions respond to changes in biorepository regulation.

Background: Azithromycin has been associated with abnormalities of cardiac repolarization and development of torsades de pointes. Observational data suggest that the risk of death from cardiovascular causes is increased in patients taking azithromycin. Little is known regarding the risk of ventricular arrhythmia in patients with prolongation of the corrected QT interval who receive azithromycin., Objective: The purpose of this study was to determine the incidence of sustained ventricular tachycardia in patients with prolonged corrected QT (QTc) who subsequently received azithromycin., Methods: We performed a retrospective cohort analysis of the incidence of sustained ventricular tachycardia in patients with prolonged QTc (greater than 450 ms) who successively received intravenous (IV) and/or oral azithromycin. Patients hospitalized in a tertiary care teaching hospital between November 2009 and June 2012 were included in the study. The primary outcome was sustained ventricular tachycardia documented in patients on telemetry., Results: Of the 103 patients enrolled in the study, only one patient experienced the primary outcome (0.97 %). The event occurred 1 day after the administration of a single dose of 500 mg IV azithromycin., Conclusion: The risk of sustained ventricular tachycardia was 0.97 % in our cohort of patients with prolonged QTc who subsequently received azithromycin. Given the small size of this study, additional research is needed to determine the true incidence of arrhythmia in the population.

Aim: Patent foramen ovale (PFO) is a common atrial septal defect that is largely asymptomatic and often undiagnosed. The impact of a PFO in patients undergoing liver transplantation (LT) is unknown., Objective: Assess the impact of PFO and physiologic intrapulmonary shunt (IPS) on the perioperative outcomes of patients who underwent LT., Methods: We performed a retrospective, intention-to-treat analysis of patients with PFO and controls without PFO who underwent LT at Mayo Clinic in Florida between 2008 and 2013. Patients with physiologic IPS were also analyzed. The cohorts were compared for baseline characteristics, length of stay in the intensive care unit (ICU), postoperative oxygen requirements, 30-d cerebrovascular accidents, and mortality., Results: Of the 935 patients who underwent LT, 10.4% had proven PFO by pre-LT echocardiogram. Control patients (n = 101) were statistically older than PFO and IPS (n = 56) patients, but similar in sex, BMI, Model for End-stage Liver Disease score, American Society of Anesthesiologist score, and left ventricular ejection fraction. PFO and IPS patients had similar length of stay in the ICU, mechanical ventilation times, post-LT oxygen requirements, and 30-d mortality compared to controls. Subgroup analysis showed similar outcomes for large PFO and IPS patients to controls., Conclusions: The presence of PFO did not have a negative impact on perioperative LT outcomes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biorepositories, or biobanks, provide researchers with access to biological samples and associated data in support of translational research. Efficient operation and ethical stewardship of biobanks involves coordinated efforts among multiple stakeholders including researchers who manage and use the repository, institutional officials charged with its oversight, and patients and volunteers who contribute samples and data. As advancements in translational research increasingly involve more data derived from larger numbers of diverse samples, the size and governance challenges facing biorepositories have grown. We describe an approach to developing efficient and ethical biobank governance that includes all major stakeholders. This model provides a pathway for addressing the technical and ethical challenges that must be resolved to ensure biorepositories continue to support translational research., (© 2015 Wiley Periodicals, Inc.)

Gratitude has robust associations with multiple aspects of well-being. However, little research has explored whether the psychological benefits of gratitude extend to body image. We used a repeated measures experimental design to test whether a brief period of grateful reflection would buffer the adverse effect of exposure to thin-ideal media. Female undergraduates (N=67) completed three sessions one week apart. The conditions were specifically designed to isolate (a) the effects of viewing thin models on body dissatisfaction and (b) the moderating effect of grateful contemplation. Results showed that body dissatisfaction scores were lower for women who engaged in a brief period of grateful contemplation before viewing photographs of thin models than for women who reflected upon life hassles before viewing the same photographs. The magnitude of this decrease depended on BMI. Gratitude offers an innovative direction for future research directed toward helping women to accept their bodies., (Copyright © 2014. Published by Elsevier Ltd.)

Introduction: Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that healthcare recommendations are informed by the best available research evidence. This is the fourth of a series of 14 articles prepared to advise guideline developers in respiratory and other disease. It focuses on commercial funding of guidelines and managing conflict of interest effectively in the context of guidelines., Methods: In this review, we addressed the following topics and questions. (1) How are clinical practice guidelines funded? (2) What are the risks associated with commercial sponsorship of guidelines? (3) What relationships should guideline committee members be required to disclose? (4) What is the most efficient way to obtain complete and accurate disclosures? (5) How should disclosures be publicly shared? (6) When do relationships require management? (7) How should individual conflicts of interest be managed? (8) How could conflict of interest policies be enforced? The literature review included a search of PubMed and other databases for existing systematic reviews and relevant methodological research. Our conclusions are based on available evidence, consideration of what guideline developers are doing, and workshop discussions., Results and Discussion: Professional societies often depend on industry funding to support clinical practice guideline development. In addition, members of guideline committees frequently have financial relationships with commercial entities, are invested in their intellectual work, or have conflicts related to clinical revenue streams. No systematic reviews or other rigorous evidence regarding best practices for funding models, disclosure mechanisms, management strategies, or enforcement presently exist, but the panel drew several conclusions that could improve transparency and process.

Experiments conducted in three almond, Prunus dulcis (Rosales: Rosaceae), orchards and three pistachio, Pistacia vera (Sapindales: Anicardiaceae), orchards in 2009 and 2010, and determined that sticky bottom wing traps baited with ground pistachio mummies, or a combination of ground pistachio plus ground almond mummies, trapped more adult female navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), than did traps baited with ground almond mummies alone. During both years of this study, 2.9 and 1.8 more moths were caught in traps baited with pistachio mummies compared with traps baited with almond mummies in almond orchards and pistachio orchards, respectively. Also, traps located in pistachio orchards caught 5.9 and 8.3 times more navel orangeworm than were trapped from almond orchards in 2009 and 2010, respectively. Implications for use of this novel baited trap in almond and pistachio orchard integrated pest management programs are discussed.

Objective: Physicians and surrogate decision-makers for seriously ill patients often have different views of patients' prognoses. We sought to understand what sources of knowledge surrogates rely on when estimating a patient's prognosis., Design: Prospective, mixed-methods study using face-to-face, semistructured interviews with surrogate decision-makers., Setting: Four intensive care units at the University of California, San Francisco Medical Center in 2006 to 2007., Participants: Participants were 179 surrogate decision-makers for 142 incapacitated, critically ill patients at high risk for death., Main Results: Less than 2% (3 of 179) of surrogates reported that their beliefs about the patients' prognoses hinged exclusively on prognostic information provided to them by physicians. The majority cited other factors in addition to physicians' predictions that also contributed to their beliefs about the patients' prognoses, including perceptions of the patient's individual strength of character and will to live; the patient's unique history of illness and survival; the surrogate's own observations of the patient's physical appearance; the surrogate's belief that their presence at the bedside may improve the prognosis; and the surrogate's optimism, intuition, and faith. For some surrogates, these other sources of knowledge superseded the importance of the physician's prognostication. However, most surrogates endeavored to balance their own knowledge of the patient with physicians' biomedical knowledge., Conclusions: Surrogates use diverse types of knowledge when estimating their loved ones' prognoses, including individualized attributes of the patient, such as their strength of character and life history, of which physicians may be unaware. Attention to these considerations may help clinicians identify and overcome disagreements about prognosis.

A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.

The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.

3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.

Background: Although many physicians worry that openly discussing a poor prognosis will cause patients and families to lose hope, surrogate decision makers' perspectives on this topic are largely unknown., Objective: To determine surrogate decision makers' attitudes toward balancing hope and telling the truth when discussing prognosis., Design: Prospective, mixed-methods cohort study., Setting: 4 intensive care units at the University of California, San Francisco, Medical Center, San Francisco, California., Participants: 179 surrogate decision makers for incapacitated patients at high risk for death., Measurements: One-on-one, semistructured interviews with surrogates were conducted on the patients' 5th day of receiving mechanical ventilation. Constant comparative methods were used to inductively develop a framework to describe participants' responses. Validation methods included multidisciplinary analysis and member checking., Results: Overall, 93% (166 of 179) of surrogates felt that avoiding discussions about prognosis is an unacceptable way to maintain hope. The main explanatory theme was that timely discussion of prognosis is essential to allow family members to prepare emotionally and logistically for the possibility of a patient's death. Other themes that emerged included surrogates' belief that an accurate understanding of a patient's prognosis allows them to better support the patient and each other, a moral aversion to the idea of false hope, the perception that physicians have an obligation to discuss prognosis, and the notion that some surrogates look to physicians primarily for truth and seek hope elsewhere. A few surrogates (6 of 179) felt that physicians should withhold prognostic information because of a belief that discussing death could be emotionally damaging to the family or could negatively affect the patient's health., Limitation: The authors did not longitudinally assess whether early disclosure about prognosis predicts fewer adverse bereavement outcomes., Conclusion: Most surrogates of critically ill patients do not view withholding prognostic information as an acceptable way to maintain hope, largely because timely discussions about prognosis help families begin to prepare emotionally, existentially, and practically for the possibility that a patient will die.

A small family of phenyl quinazolinone ureas is reported as potent modulators of Hedgehog protein function. Preliminary SAR studies of the urea substituent led to a nanomolar Hedgehog antagonist.

Background: Forthright reporting of financial ties and conflicts of interest of researchers is associated with public trust in and esteem for the scientific enterprise., Methods/principal Findings: We searched Lexis/Nexis Academic News for the top news stories in science published in 2004 and 2005. We conducted a content analysis of 1152 newspaper stories. Funders of the research were identified in 38% of stories, financial ties of the researchers were reported in 11% of stories, and 5% reported financial ties of sources quoted. Of 73 stories not reporting on financial ties, 27% had financial ties publicly disclosed in scholarly journals., Conclusions/significance: Because science journalists often did not report conflict of interest information, adherence to gold-standard recommendations for science journalism was low. Journalists work under many different constraints, but nonetheless news reports of scientific research were incomplete, potentially eroding public trust in science.

Despite a decade of federal regulation and debate over the appropriateness of financial ties in research and their management, little is known about the actual decision-making processes of university conflict of interest (COI) committees. This paper analyzes in detail the discussions and decisions of three COI committees at three public universities in California. University committee members struggle to understand complex financial relationships and reconcile institutional, state, and federal policies and at the same time work to protect the integrity of the scientific process, the autonomy and intellectual freedom of their faculty colleagues and students, and the financial interests of the university.

Background: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the fourth of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this., Objectives: We reviewed the literature on conflicts of interest to answer the following questions: 1. What is the best way to obtain complete and accurate disclosures on financial ties and other competing interests? 2. How to determine when a disclosed financial tie or other competing interest constitutes a conflict of interest? 3. When a conflict of interest is identified, how should the conflict be managed? 4. How could conflict of interest policies be enforced?, Methods: We searched PubMed, the Cochrane Methodology Register and selectively searched for the published policies of several organizations, We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments., Key Questions and Answers: What is the best way to obtain complete and accurate disclosures on financial ties and other competing interests? Although there is little empirical evidence to guide the development of disclosure forms, minimal or open-ended formats are likely to be uninformative. We recommend the development of specific, detailed, structured forms that solicit as much information as possible about the nature and extent of the competing interests. How to determine when a disclosed financial tie or other competing interest constitutes a conflict of interest?* There is no empirical evidence to suggest that explicit criteria are preferable to ad hoc committee decisions when deciding if a disclosed financial tie is a conflict of interest. However, explicit criteria may make decision-making easier. When a conflict of interest is identified, how should the conflict be managed? Descriptive studies suggest that appropriate management strategies are best determined on a case-by-case basis. Thus, WHO should use a wide range of management strategies to address disclosed conflicts of interest, with public disclosure of conflicts associated with each meeting as a minimum and recusal of conflicted individuals as the other extreme. How could conflict of interest policies be enforced? Although there are no empirical studies of the enforcement of conflict if interest policies, descriptive studies of other organizations and institutions suggest that WHO convene a standing committee to review all financial disclosure statements prior to the commencement of committee meetings/hearings and to make management recommendations when necessary. A standard policy requiring all financial ties to be made public (i.e., recorded into the meeting minutes) should reduce the number of problematic cases. In instances where the conflicts seem intractable, a recommendation of recusal may be necessary to protect the greater interests of WHO and its constituents.

Objective: To identify characteristics of submitted manuscripts that are associated with acceptance for publication by major biomedical journals., Design, Setting and Participants: A prospective cohort study of manuscripts reporting original research submitted to three major biomedical journals (BMJ and the Lancet [UK] and Annals of Internal Medicine [USA]) between January and April 2003 and between November 2003 and February 2004. Case reports on single patients were excluded., Main Outcome Measures: Publication outcome, methodological quality, predictors of publication., Results: Of 1107 manuscripts enrolled in the study, 68 (6%) were accepted, 777 (70%) were rejected outright, and 262 (24%) were rejected after peer review. Higher methodological quality scores were associated with an increased chance of acceptance (odds ratio [OR], 1.39 per 0.1 point increase in quality score; 95% CI, 1.16-1.67; P < 0.001), after controlling for study design and journal. In a multivariate logistic regression model, manuscripts were more likely to be published if they reported a randomised controlled trial (RCT) (OR, 2.40; 95% CI, 1.21-4.80); used descriptive or qualitative analytical methods (OR, 2.85; 95% CI, 1.51-5.37); disclosed any funding source (OR, 1.90; 95% CI, 1.01-3.60); or had a corresponding author living in the same country as that of the publishing journal (OR, 1.99; 95% CI, 1.14-3.46). There was a non-significant trend towards manuscripts with larger sample size (>/= 73) being published (OR, 2.01; 95% CI, 0.94-4.32). After adjustment for other study characteristics, having statistically significant results did not improve the chance of a study being published (OR, 0.83; 95% CI, 0.34-1.96)., Conclusions: Submitted manuscripts are more likely to be published if they have high methodological quality, RCT study design, descriptive or qualitative analytical methods and disclosure of any funding source, and if the corresponding author lives in the same country as that of the publishing journal. Larger sample size may also increase the chance of acceptance for publication.

Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.

Few studies have examined academic researchers' understandings or attitudes toward conflict of interest policies even though these understandings and attitudes represent a crucial component of both compliance and educational efforts. This study reports the results of a large-scale, cross-sectional survey of research faculty at the nine campuses of the University of California regarding their understandings of and attitudes toward campus conflict of interest policies. We gathered information on their general assessments of investigators with financial ties to industry sponsors and reactions to the process of implementing conflict of interest policies at their respective campuses. We surveyed 1,971 faculty members from the nine-campus University of California system and had 779 responses (39% response rate). The sampled faculty were in the ten departments with the most number of financial disclosures at each campus. We utilized the WebSurveyor software to create a secure, online, 21-item survey. Our study reveals faculty with complex, sometimes contradictory, feelings about academic-industry relationships and highlights perceived gaps in policy and process. Most respondents were concerned about unlimited financial relationships, but a sizable number also viewed campus policies as irrelevant. Some expressed considerable anger over the process of policy implementation, rejecting the policies on the basis of professional and individual self-determination and moral integrity. Our study suggests the need for renewed efforts to encourage awareness of the relevance of conflict of interest policies for all faculty, new efforts to increase understanding of the situational nature of conflicts of interest, and reexamination of the processes of policy implementation at the campus level.

Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.

Amid concerns that clinical and basic research is increasingly vulnerable to pressure from industry sponsors, many federal agencies and professional organizations are recommending new or revised policies regardingfinancial disclosure and conflicts of interest. Despite pressure for greater external regulation and common professional standards, little is known about how existing policies are implemented. We analyze the implementation of conflict-of-interest policies within the multicampus University of California system. We show that there is variation among campuses in defining problematic relationships and in determining appropriate remedies to mitigate conflicts of interest. Our study suggests the importance of local culture and context for institutional decision making.

As industry sponsorship of clinical research grows, investigators' personal financial relationships with those sponsors are under increasing scrutiny. The federal government, some states, and many universities have enacted conflict-of-interest policies to monitor and regulate investigators' financial relationships. Little is known, however, about investigators' awareness of or support for these policies or their attitudes toward regulatory efforts. To explore the possible implications of conflict-of-interest policies for clinical researchers, the authors interviewed active clinical investigators at two institutions where the conflict-of-interest policies differ. The most striking feature of the interviews was the range of perceptions and attitudes expressed by clinical investigators and their implications for administrators, professional societies, and policymakers concerned with conflicts of interest. Fewer than half of the interviewed investigators could accurately describe their campus' conflict-of-interest policy. Many investigators felt that professional societies, the public, and individual investigators were appropriate monitors of conflicts of interest. Many investigators recognized the general risks associated with conflicts of interest, but felt that they personally were not at risk. A fundamental challenge facing administrators and policymakers is to demonstrate to all investigators, both clinical and nonclinical, that the potential for bias, pressure and conflict is relevant to all investigators with industry relationships.

Context: To maximize the participation rate in population genetic studies, alternatives to invasive whole blood collection are increasing. One such alternative is buccal epithelial cell collection, which, in contrast to venipuncture and finger sticks, is painless. Buccal cells, if collected and purified efficiently, offer an acceptable source for DNA to be used in research and clinical applications., Objective: To develop a noninvasive sampling method for collecting cells for routine DNA testing in a clinical laboratory setting., Design: Five factors were used to evaluate several brands of mouthwash: (1) compatibility with the DNA purification chemistry, (2) DNA yield, (3) DNA quality, (4) DNA stability at room temperature, and (5) mouthwash taste. Next, an optimization study was undertaken to maximize DNA yield. Finally, a validation study was undertaken with the optimized protocol to test a panel of 14 donors for DNA yield and performance and to test for the stability of DNA held in mouthwash., Setting: Industrial research and development laboratory., Results: Of 5 mouthwashes tested, Scope brand mouthwash received the highest overall ranking. The addition of proteinase K and glycogen to the protocol significantly enhanced DNA yields, with a test panel (n = 14) giving a range of 12 to 60 microg of DNA per donor. In a 4-week room temperature stability study, the DNA in mouthwash samples was found to be stable for at least 2 weeks., Conclusion: A clinically validated DNA purification chemistry was adapted to a noninvasive specimen collection method. This method used a commercially available mouthwash, Scope, to collect buccal epithelial cells for the preparation of high-quality DNA in high yield.

Context: A growing number of academic researchers receive industry funding for clinical and basic research, but little is known about the personal financial relationships of researchers with their industry sponsors., Objectives: To assess the extent to which faculty researchers have personal financial relationships with the sponsors of their research, the nature of those financial relationships, and efforts made at the institutional level to address disclosed financial relationships and perceived conflicts of interest., Design and Setting: Case study of the University of California, San Francisco (UCSF). Data sources included disclosure forms and official documents maintained by the UCSF Office of Research Administration from December 1980 to October 1999, including decisions made by the UCSF Chancellor's Advisory Panel on Relations with Industry., Main Outcome Measures: Number and types of personal financial relationships with external sponsors (positive financial disclosures from all clinical, basic, or social science faculty who were principal investigators), amount of annual income received from sponsors, and decisions and management strategies used by the advisory panel., Results: By 1999, almost 7.6% of faculty investigators reported personal financial ties with sponsors of their research. Throughout the study period, 34% of disclosed relationships involved paid speaking engagements (range, $250-$20, 000 per year), 33% involved consulting agreements between researcher and sponsor (range, <$1000-$120,000 per year), and 32% involved the investigator holding a position on a scientific advisory board or board of directors. Fourteen percent involved equity ownership, and 12% involved multiple relationships. The advisory panel recommended managing perceived conflicts of interest in 26% of the cases, including recommending the sale of stock, refusing additional payment for talks, resigning from a management position, or naming a new principal investigator for a project., Conclusions: Faculty researchers are increasingly involved in financial relationships with their research sponsors. Guidelines for what constitutes a conflict and how the conflict should be managed are needed if researchers are to have consistent standards of behavior among institutions. JAMA. 2000;284:2209-2214.

Using the endogenous cannabinoid receptor agonist anandamide, the synthetic agonist CP 55940 [[1alpha,2beta(R)5alpha]-(-)-5-(1,1-dimethylheptyl+ ++)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and the specific antagonist SR 141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], second messenger activation of the central cannabinoid receptor (CB1) was examined in rat striatal and cortical slices. The effects of these cannabinoid ligands on electrically evoked dopamine (DA) release from [3H] dopamine-prelabelled striatal slices were also investigated. CP 55940 (1 microM) and anandamide (10 microM) caused significant reductions in forskolin-stimulated cyclic AMP accumulation in rat striatal slices, which were reversed in the presence of SR 141716 (1 microM). CP 55940 (1 microM) had no effect on either KCl- or neurotransmitter-stimulated 3H-inositol phosphate accumulation in rat cortical slices. CP 55940 and anandamide caused significant reductions in the release of dopamine after electrical stimulation of [3H]dopamine-prelabelied striatal slices, which were antagonised by SR 141716. SR 141716 alone had no effect on electrically evoked dopamine release from rat striatal slices. These data indicate that the CB1 receptors in rat striatum are negatively linked to adenylyl cyclase and dopamine release. That the CB1 receptor may influence dopamine release in the striatum suggests that cannabinoids play a modulatory role in dopaminergic neuronal pathways.

Context: Utilization review (UR) seeks to improve quality and cost-efficiency of health care. However, how well the process works in practice has not been assessed., Objective: To describe the outcomes of a sample of physician reviews in terms of the explicit criteria that the UR was designed to implement., Design: Retrospective analysis of transcripts of precertification reviews., Participants and Setting: California physicians employed by a UR firm conducted 96 interviews from April 1990 to July 1991 with attending physicians who had proposed to insert tympanostomy tubes on a patient younger than 16 years and whose proposals had been found to be inappropriate on an initial screen., Main Outcome Measures: The appropriateness rating assigned to each case by the physician-reviewer and by the investigators using explicit criteria. Logistic regression identified factors associated with the reviewers' recommendations to perform surgery and with recommendations at variance from the criteria., Results: The reviewers recommended 78% of cases for surgery, of which only 29% were supported by the criteria or had extenuating circumstances. The criteria concurred with all 30 of the reviewers' recommendations against surgery. Two factors, female sex (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.2-53.8) and previous tympanostomy tube insertion (OR, 30.9; 95% CI, 2.4-394.8) were associated with reviewer recommendations in favor of surgery that were at variance from the criteria, despite the lack of evidence for either as a mitigating circumstance., Conclusion: Physician reviewers were more lenient than the explicit criteria that the reviews were designed to implement. In no cases did the reviewers depart from the criteria's recommendations in favor of surgery.

Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there is an additional endothelial relaxant factor, termed the endothelium-derived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is thought to be an arachidonic acid metabolite. We now report that EDHF-mediated relaxations in the rat mesenteric arterial bed are blocked by a highly selective cannabinoid receptor antagonist, SR141716A, consistent with EDHF being a cannabinoid-like substance. Furthermore, in conscious rats,. the NO-independent depressor and regional vasodilator effects of bradykinin were inhibited by SR141716A. The relaxations in the isolated mesentery were accompanied by the accumulation of an arachidonic acid metabolite, which co-eluted on TLC separation with arachidonoylethanolamide (anandamide), an endogenous cannabinoid derived from arachidonate. We further report that anandamide is a potent vasorelaxant in the mesentery, acting via a hyperpolarizing mechanism. These findings suggest that an endogenous cannabinoid is an endothelium-derived vasorelaxant, which may be EDHF.

The behavioural effects of an extract of Cassia siamea, a plant used in Thai traditional medicine, and barakol, its active chemical, were studied on an elevated plus-maze compared with diazepam. An aqueous extract of C. siamea (1, 6, and 12 g/kg body wt., orally) produced a small increase in the percentage of the open: total number of arm entries and time, time spent on the end of the open arms, total number of arm entries, and number of rears/min. Barakol [10 mg/kg, intraperitoneally (IP)] significantly increased all of these behavioural parameters in a manner similar to diazepam (1 mg/kg, IP, 30 or 60 min before testing), except that barakol and not diazepam increased both the number of rears and total arm entries. Barakol at 25 and 50 mg/kg increased the percentage of the open: total number of arm entries and time and number of rears. The results indicate that barakol has anxiolytic properties similar to diazepam but differs from diazepam in that it also increases exploratory and locomotor behaviour, as shown by the number of rears and total arm entries.

This study describes the reliability and validity of a new radiological method to measure shoulder subluxation that is based on taking a single x-ray of the affected shoulder in the plane of the scapula. A digitizer and a computer are used to quantify the measurements directly from the x-ray. One single radiological view of the shoulder taken in a standardized position provides four measures of subluxation including a measure of vertical subluxation, horizontal subluxation, a normalized distance sensitive to both vertical and horizontal subluxation, and an angular measure. A total of 72 volunteers with cerebrovascular accidents participated in the study. Thirty-six subjects had a clinical shoulder subluxation and 36 had no clinical subluxation. The construct validity analysis showed significant differences (p < .001) between the mean scores for subluxed and nonsubluxed groups on all four measures of subluxation. The concurrent validity of the x-ray measures in relation to external clinical measures (finger's breadth, measures in centimeters with calipers or a plexiglass jig) was moderate. Three measures were found to be reliable and valid whereas the fourth, a measure of horizontal subluxation has lower reliability. However, it does have clinical significance. The clinical and research implications of this study are presented.

The purpose of this report is to describe the reliability of three clinical measures used to evaluate changes in shoulder subluxation. The three methods include measuring the subacromial space in fingers breadth, using calipers, or a plexiglass jig. Thirty-six patients with shoulder subluxation who had experienced a cerebrovascular accident were the subjects. Four occupational therapists with experience in stroke rehabilitation were divided into two teams of two therapists and rated the subjects independently. Each rater repeated her assessments on nine subjects to test intrarater agreement. Inter-rater agreement was assessed both between members of the same team (27 subjects per rater pair) and members of different teams (18 subjects per rater pair). The measure of reliability was the intraclass correlation coefficient (ICC2, 1) as derived from two-way analysis of variance. The highest intra-rater reliability was displayed by the finger breadth method, the second highest by the caliper method and the lowest by the plexiglass jig. The coefficients in the former two cases were always above .8. Using the jig only one rater achieved this level. Agreement between the two members of the same team were above .75 for the fingers and caliper methods, but less than this for the jig. Between members of different teams however, only the finger breadth method attained reliabilities above .7, and the plexiglass jig, in particular, showed very low reliability. These results demonstrate the difficulty of achieving consistent clinical measurement for a condition like shoulder subluxation.(ABSTRACT TRUNCATED AT 250 WORDS)