Search

Context Signature informed consent (SIC) is a part of a Veterans Health Administration ethics initiative for patient education and shared decision making with long-term opioid therapy (LTOT). Historically, patients with cancer-related pain receiving LTOT are exempt from this process. Objectives Our objective is to understand patients' and providers' perspectives on using SIC for LTOT in patients with cancer-related pain. Methods Semistructured interviews with 20 opioid prescribers and 20 patients who were prescribed opioids at two large academically affiliated Veterans Health Administration Medical Centers. We used a combination of deductive and inductive approaches in content analysis to produce emergent themes. Results Potential advantages of SIC are that it can clarify and help patients comprehend LTOT risks and benefits, provide clear upfront boundaries and expectations, and involve the patient in shared decision making. Potential disadvantages of SIC include time delay to treatment, discouragement from recommended opioid use, and impaired trust in the patient-provider relationship. Providers and patients have misconceptions about the definition of SIC. Providers and patients question if SIC for LTOT is really informed consent. Providers and patients advocate for strategies to improve comprehension of SIC content. Providers had divergent perspectives on exemptions from SIC. Oncologists want SIC for LTOT to be tailored for patients with cancer. Conclusion Provider and patient interviews highlight various aspects about the advantages and disadvantages of requiring SIC for LTOT in cancer-related pain. Tailoring SIC for LTOT to be specific to cancer-related concerns and to have an appropriate literacy level are important considerations.

The Ethics Consultation Quality Assessment Tool (ECQAT) establishes standards by which the quality of ethics consultation records (ECRs) can be assessed. These standards relate to the ethics question, consultation-specific information, ethical analysis, and recommendations and/or conclusions, and result in a score associated with one of four levels of ethics consultation quality. For the ECQAT to be useful in assessing and improving the quality of healthcare ethics consultations, individuals who rate the quality of ECRs need to be able to reliably use the tool. We developed a short course to train ethics consultants in using the ECQAT, and evaluated whether the participants (1) achieved an acceptable level of calibration in matching expert-established quality scores for a set of ethics consultations, and (2) were satisfied with the course. We recruited 28 ethics consultants to participate in a virtual, six-session course. At each session participants and faculty reviewed, rated, and discussed one to two ECRs. The participants' calibration in matching expert-established quality scores improved with repeated exposure at all levels of ethics consultation quality. Participants were generally more accurate when assessing consultation quality at the dichotomous level of "acceptable" (scores of three or four) versus "unacceptable" (scores of one or two) than they were with more a specific score. Participants had higher rates of accuracy with the extreme ratings of "strong" (level four) or "poor" (level one). Although participants were highly satisfied with the course, only a minority of participants achieved the prespecified acceptable level of calibration (that is, 80 percent or greater accuracy between their score and expert-established scores). These results suggest that ECQAT training may require more sessions or need modification in the protocol to achieve higher reliability in scoring. Such trainings are an important next step in ensuring that the ECQAT is a tool that can be used to promote improvement in ethics consultation quality.

This paper analyzes the phenomenon of suffering and its relationship to medical practice by focusing on the paradigmatic work of Eric Cassell. First, it explains Cassell's influential model of suffering. Second, it surveys various critiques of Cassell. Next it outlines the authors' concerns with Cassell's model: it is aggressive, obscure, and fails to capture important features of the suffering experience. Finally, the authors propose a conceptual framework to help clarify the distinctive nature of subjective patient suffering. This framework contains two necessary conditions: (1) a loss of a person's sense of self, and (2) a negative affective experience. The authors suggest how this framework can be used in the medical encounter to promote clinician-patient communication and the relief of suffering.

Although clinical ethics consultation is a high-stakes endeavor with an increasing prominence in health care systems, progress in developing standards for quality is challenging. In this article, we describe the results of a pilot project utilizing portfolios as an evaluation tool. We found that this approach is feasible and resulted in a reasonably wide distribution of scores among the 23 submitted portfolios that we evaluated. We discuss limitations and implications of these results, and suggest that this is a significant step on the pathway to an eventual certification process for clinical ethics consultants.

Healthcare organizations with an ethical culture experience higher levels of employee productivity, less staff turnover, better levels of patient safety, resource and cost savings, and higher levels of patient satisfaction. Employees' perceptions of the ethics of their organization are considered a good indicator of the ethics culture. How employees rate the ethics of their organization is not well understood. Previous research has identified a number of attributes that are salient to employees' perceptions in this area. However, little is known about how employees synthesize their perceptions of these attributes to rate the ethics of their organization. Without this knowledge, managers have little specific information to act on to improve practices that would in turn improve employees' perceptions of their organization's ethics. For this study, we used data from Department of Veterans Affairs' (VA) 2014 IntegratedEthics@ Staff Survey administered to Veterans Health Administration (VHA) staff. We used multivariate regression analyses to investigate how VHA employees weigh their perceptions of eight attributes of an ethical organization to inform an overall rating of the ethics of their organization. We found that employee perceptions of fairness, clarity of expectations, accountability, and leadership's prioritization of ethics had the strongest associations with the overall rating. In addition, employees disproportionately weighed their positive perceptions in determining their overall rating. Therefore, a strategy to improve employees' perceptions of these attributes could potentially have the greatest marginal return on investment with respect to improving employees' perceptions of the ethics of an organization.

As documented clearly by Nie and colleagues (2016), the fields of health care and biomedical research are saturated with metaphor. One can hardly spend 10 minutes on a hospital ward, in a discussio...

Clinical ethics consultation is largely outside the scope of regulation and oversight, despite its importance. For decades, the bioethics community has been unable to reach a consensus on whether there should be accountability in this work, as there is for other clinical activities that influence the care of patients. The American Society for Bioethics and Humanities, the primary society of bioethicists and scholars in the medical humanities and the organizational home for individuals who perform CEC in the United States, has initiated a two-step quality attestation process as a means to assess clinical ethics consultants and help identify individuals who are qualified to perform this role. This article describes the process.

Background: To improve ethics quality in health care, health care organizations need a way to characterize whether ethical practices throughout the organization are consistent with accepted ethics standards, norms, and expectations for the organization and its staff. We developed the IntegratedEthics™ Staff Survey (IESS) to fill this need. Methods: The IESS was developed and validated through a rigorous multiyear process. This process included reviews of the bioethics and health care literature to develop conceptual maps of common ethical issues in health care; focus groups and interviews with institutional stakeholders to identify key ethical concerns; cognitive testing, pilot testing, and field testing to ensure that questions were understandable and useful; and item reduction and modification to reduce respondent burden. Results: The IESS addresses staff perceptions of ethical practices in nine domains: everyday workplace, business and management, government service, patient privacy and confidentiality...

Background: To enhance understanding of ethical leadership and the ethical environment and culture (EL/EEC) in the Department of Veterans Affairs (VA) health care system, we mapped selected questions from the VA IntegratedEthics™ Staff Survey (IESS), a national survey of employees’ perceptions of ethical practices, to the Ethical Leadership Compass Points (ELC), a tool to help leaders cultivate an environment and culture that makes it easy for employees to “do the right thing.” The ELC distills insights and principles from organizational and business ethics and provides leaders with specific behaviors that can be incorporated into daily administrative routines. Methods: We analyzed the responses of 88,605 VA employees to the 2010 IESS questions that previously were mapped to the ELC. Descriptive statistics were used to characterize overall distribution of responses to the survey questions, and Pearson's chi-squared tests were performed to assess differences in responses by employee characteristics. Multi...

Background: IntegratedEthicsTM (IE) establishes a new model for ethics programs, with the goal of continuously improving “ethics quality” in health care. This article describes the IntegratedEthics Facility Workbook (IEFW), an evaluation tool developed by the National Center for Ethics in Health Care (NCEHC) to help health care facilities improve ethics quality in their organization. The workbook helps facilities to evaluate their local ethics programs relative to specific quality standards established for the IE model. This article describes the origins of the quality standards established for the IE model, explains IEFW conceptual underpinnings and tool development, illustrates how ethics programs use the tool to drive local program quality improvement, and provides longitudinal IEFW national results (2008–2011) for Department of Veterans Affairs (VA) IE programs. Methods: The project uses descriptive analysis of IEFW data submitted by VA facilities from 2008 through 2011. Results: In VA, longitudinal I...

Although ethics consultation is offered as a clinical service in most hospitals in the United States, few valid and practical tools are available to evaluate, ensure, and improve ethics consultation quality. The quality of ethics consultation is important because poor quality ethics consultation can result in ethically inappropriate outcomes for patients, other stakeholders, or the health care system. To promote accountability for the quality of ethics consultation, we developed the Ethics Consultation Quality Assessment Tool (ECQAT). ECQAT enables raters to assess the quality of ethics consultations based on the written record. Through rigorous development and preliminary testing, we identified key elements of a quality ethics consultation (ethics question, consultation-specific information, ethical analysis, and conclusions and/or recommendations), established scoring criteria, developed training guidelines, and designed a holistic assessment process. This article describes the development of the ECQAT, the resulting product, and recommended future testing and potential uses for the tool.

Background: The traditional approach to resolving ethics concerns may not address underlying organisational issues involved in the evolution of these concerns. This represents a missed opportunity to improve quality of care “upstream”. The purpose of this study was to understand better which organisational issues may contribute to ethics concerns. Methods: Directed content analysis was used to review ethics consultation notes from an academic children’s hospital from 1996 to 2006 (N = 71). The analysis utilised 18 categories of organisational issues derived and modified from published quality improvement protocols. Results: Organisational issues were identified in 68 of the 71 (96%) ethics consult notes across a range of patient settings and reasons for consultation. Thirteen of the 18 categories of organisational issues were identified and there was a median of two organisational issues per consult note. The most frequently identified organisational issues were informal organisational culture (eg, collective practices and approaches to situations with ethical dimensions that are not guided by policy), policies and procedures (eg, staff knows policy and/or procedural guidelines for an ethical concern but do not follow it) and communication (eg, communication about critical information, orders, or hand-offs repeatedly does not occur among services). Conclusions: Organisational issues contribute to ethical concerns that result in clinical ethics consults. Identifying and addressing organisational issues such as informal culture and communication may help decrease the recurrence of future similar ethics concerns.

Although ethics consultation is commonplace in United States (U.S.) hospitals, descriptive data about this health service are lacking.To describe the prevalence, practitioners, and processes of ethics consultation in U.S. hospitals.A 56-item phone or questionnaire survey of the "best informant" within each hospital.Random sample of 600 U.S. general hospitals, stratified by bed size.The response rate was 87.4%. Ethics consultation services (ECSs) were found in 81% of all general hospitals in the U.S., and in 100% of hospitals with more than 400 beds. The median number of consults performed by ECSs in the year prior to survey was 3. Most individuals performing ethics consultation were physicians (34%), nurses (31%), social workers (11%), or chaplains (10%). Only 41% had formal supervised training in ethics consultation. Consultation practices varied widely both within and between ECSs. For example, 65% of ECSs always made recommendations, whereas 6% never did. These findings highlight a need to clarify standards for ethics consultation practices.

We interviewed 71 surrogate decision makers of older, chronically ill veterans to explore their knowledge of hospice and their role in helping loved ones access hospice services. We asked them to describe hospice and any previous hospice experiences. Qf the group, 24 percent with hospice experience and 14 percent without hospice experience correctly described three key aspects of hospice: who hospice cares for, where the care is provided, and the goal of the care. Additionally, we found evidence that surrogates who correctly described the three key aspects of hospice were inclined to pursue hospice care for loved ones in the future, and surrogates who provided less complete descriptions of hospice might not access it. Since surrogates often help dying patients access care, incomplete knowledge of hospice may be an important barrier to hospice services. We advocate that clinicians discuss the three key aspects of hospice during routine advance care planning sessions with patients and their future surrogate decision makers.

Purpose To analyze the clinical characteristics and treatment outcomes of patients with bleb-associated endophthalmitis (BAE). Design Retrospective, noncomparative, interventional case series. Participants Consecutive patients treated at one institution for BAE. Interventions Prompt pars plana vitrectomy (PPV) with intravitreal injection of antibiotics, or prompt vitreous biopsy and intravitreal injection of antibiotics (tap and inject). Methods Retrospective analysis of 68 consecutive cases of BAE between July 1, 1989 and June 30, 2001. Clinical presentation, treatment modality, microbiologic data, and clinical course were analyzed. Visual outcomes were compared between vitrectomy and tap-and-inject groups, culture-positive and culture-negative groups, and early and late times. Main outcome measures Snellen visual acuities (VAs) at 3 months and 12 months after treatment and at most recent follow-up. Results The incidence of no light perception (NLP) at 12 months after treatment for BAE was 35%. Vitreous isolates included streptococcal species (32% of positive cultures), Staphylococcus epidermidis (26%), Enterococcus , and Serratia (12% each). Patients with a positive vitreous culture had significantly worse VA (median, hand movements [HM] at 3 and 12 months after treatment) and a higher rate of NLP vision. Patients treated with tap-and-inject had a significantly worse final VA (medians, HM at 3 months and LP at 12 months) and a significantly higher rate of NLP vision than patients treated with PPV. One third of patients who underwent PPV achieved a final VA of 20/100 or better 12 months after treatment ( P = 0.09). Conclusions Bleb-associated endophthalmitis causes significant visual morbidity. Patients with culture-negative BAE and patients treated with prompt PPV may achieve better visual outcome.

Physician-assisted suicide (PAS) has attracted considerable professional attention in recent years in the end-of-life care debate. The role of depression and other psychiatric illnesses on the patient's pursuit of PAS is unclear. As part of a qualitative study exploring the motivations, deliberations, and complications experienced by persons with incurable diseases who were actively seeking PAS, we conducted semistructured interviews that were reviewed for psychiatric content. In total, 159 interviews were conducted with 60 participants concerning 12 prospective cases (12 patients and 20 family members) and 23 retrospective cases (28 family members), with more than 3600 pages of transcripts. Depressive symptoms, when present, were not described by the subjects and/or their family members to be an influential factor in their pursuit of PAS; no subject appeared or was described to suffer from depression-related decisional incapacity. Findings from this study, albeit from a small and self-selected sample, highlight not only the importance of avoiding a reductionistic understanding of the role of psychiatric illnesses in contributing to serious pursuit of PAS, but also the pressing need for scientifically rigorous studies of PAS in samples representative of the larger population.

Objectives: To characterize the experience of quality of life while dying from the perspective of terminally ill men. Design: Descriptive study involving semistructured interviews. Setting: Patients attending clinics at two university-affiliated medical centers were interviewed in a private conference room or in their homes. Participants: Twenty-six men identified by their physicians as having terminal heart disease or cancer. Eligible participants acknowledged that they had serious illness. Measurements: The interview contained open-ended questions such as: “What are the most important things in your life right now?” The interview also contained closed-ended questions about symptom intensity, presence of depressed mood, and other items related to overall quality of life. The open-ended questions were tape-recorded, transcribed, and analyzed using grounded theory methods. The closed-ended questions were analyzed using descriptive statistics. Results: Participants believed that death was near. Participants saw engaging in hobbies and other enjoyable activities as an alternative to moving into the final stage of illness, in which they saw themselves as actively dying. They admitted to occasionally ignoring prescribed diets; these actions improved their overall quality of life but worsened symptoms. New symptoms brought concerns about progression to active dying. They anticipated what their dying would be like and how it would affect others. Participants believed that their actions in the present could improve the quality of their dying and lessen the burden of their deaths on others. Many participants therefore were preparing for death by engaging in such tasks as putting their finances in order and planning their funerals, to relieve anticipated burden on loved ones. Conclusion: To help terminally ill patients plan for the end of life, clinicians are encouraged to become familiar with their patients' experiences of living with terminal illness, to identify each patient's unique priorities, and to incorporate that information into care plans aimed at maximizing quality of life at the end of life.

The serotonin 5HT7 receptor has been implicated in numerous physiological and pathological processes from circadian rhythms to depression and schizophrenia. Clonal cell lines heterologously expressing recombinant receptors offer good models for understanding drug-receptor interactions and development of quantitative structure-activity relationships (QSAR). Comparative Molecular Field Analysis (CoMFA) is an important modern QSAR procedure that relates the steric and electrostatic fields of a set of aligned compounds to affinity. Here, we utilized CoMFA to predict affinity for a number of high-affinity ligands at the recombinant guinea pig 5HT7 receptor. Using R-lisuride as the template, a final CoMFA model was derived using procedures similar to those of our recent papers. The final cross-validated model accounted for >85% of the variance in the compound affinity data, while the final non-cross validated model accounted for >99% of the variance. Model evaluation was done using cross-validation methods with groups of 5 ligands. Twenty cross-validation runs yielded an average predictive r2(q2) of 0.779 +/- 0.015 (range: 0.669-0.867). Furthermore, 3D-chemical database search queries derived from the model yielded hit lists of promising agents with high structural similarity to the template. Together, these results suggest a possible basis for high-affinity drug action at 5HT7 receptors.

Agonist affinity changes dramatically as a result of serine to alanine mutations (S193A, S194A, and S197A) within the fifth transmembrane region of D2 dopamine receptors and other receptors for monoamine neurotransmitters. However, agonist 2D-structure does not predict which drugs will be sensitive to which point mutations. Modeling drug-receptor interactions at the 3D level offers considerably more promise in this regard. In particular, a comparison of the same test set of agonists across receptors differing minimally (point mutations) offers promise to enhance the understanding of the structural bases for drug-receptor interactions. We have previously shown that comparative molecular field analysis (CoMFA) can be applied to comparisons of affinity at recombinant D1 and D2 dopamine receptors for the same set of agonists, a differential QSAR. Here, we predicted agonist K(L) for the same set of agonists at wild type D2 vs S193A, S194A, and S197A receptors using CoMFA. Each model used bromocriptine as the template. ln(1/K(L)) values for the low-affinity agonist binding conformation at recombinant wild type and mutant D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA of the 16 aligned agonist structures. The resulting CoMFA models yielded cross-validated R(2) (q(2)) values ranging from 0.835 to 0.864 and simple R(2) values ranging from 0.999 to 1.000. Predictions of test compound affinities at WT and each mutant receptor were close to measured affinity values. This finding confirmed the predictive ability of the models and their differences from one another. The results strongly support the idea that CoMFA models of the same training set of compounds applied to WT vs mutant receptors can accurately predict differences in drug affinity at each. Furthermore, in a "proof of principle", two different templates were used to derive the CoMFA model for the WT and S193A mutant receptors. Pergolide was chosen as an alternate template because it showed a significant increase in affinity as a result of the S193A mutation. In this instance both the bromocriptine- and pergolide-based CoMFA models were similar to one another but different from those for the WT receptor using bromocriptine- or pergolide- as templates. The pergolide-based S193A model was more strikingly different from that of the WT receptor than was the bromocriptine-based S193A model. This suggests that a "dual-template" approach to differential CoMFA may have special value in elucidating key differences across related receptor types and in determining important elements of the drug-receptor interaction.

Surrogates and clinicians often make treatment decisions for decisionally incapacitated patients with limited knowledge of their preferences. This study examined patients' life-sustaining treatment preferences to facilitate advance care planning discussions and surrogate decision making.We interviewed 342 participants from 7 groups: younger and older well adults; persons with chronic illness, terminal cancer, and acquired immunodeficiency syndrome (AIDS); stroke survivors; and nursing home residents. Preferences for antibiotics, short- and long-term mechanical ventilation, hemodialysis, tube feeding, and cardiopulmonary resuscitation (CPR) were elicited for each participant's current health state and three hypothetical health states representing severe dementia, coma, and severe stroke.Participants chose to forego more invasive or long-term treatments at a higher rate than less invasive, short-term treatments in all health states. Participants were much more willing to forego treatments in coma than in their current health state, with stroke and dementia somewhere in between. Participants who were older, female, had worse functional status, had more depressive symptoms, or lived in a nursing home were more inclined to forego treatment in their current health state. In contrast, treatment preferences in hypothetical health states showed either no associations or much weaker associations with these factors. Participants who were willing to accept more invasive treatments were highly likely to accept less invasive treatments and participants who preferred to forego a less invasive treatment were highly likely to forego more invasive treatments. Participants who preferred to receive a treatment in a health state with severe impairments were highly likely to want the same treatment in a less impaired health state. Similarly, participants who preferred to forego a treatment in a less impaired health state were highly likely to forego the same treatment in a more impaired state.In advance care planning discussions, clinicians might explore with patients their preferences about short- and long-term treatments with variability in their invasiveness (including CPR) in both their current health state and hypothetical situations representing different levels of functional impairment. When surrogates have no knowledge about the wishes of formerly competent patients, clinicians may help them with medical decisions by discussing what other people commonly want in similar circumstances.

A novel method of pharmacophore identification and activity prediction in structure-activity (structure-property) relationships is worked out as an essential extension and improvement of previous publications. In this method each conformation of the molecular systems in the training set of the SAR problem is presented by both electronic structure and geometry parameters arranged in a matrix form. Multiple comparisons of these matrices for the active and inactive compounds allows one to separate a smaller number of matrix elements that are common for all the active compounds and are not present in the same arrangement in the inactive ones. This submatrix of activity represents the pharmacophore (Pha). By introducing the Anti-Pharmacophore Shielding (APS) defined as molecular groups and competing charges outside the Pha that hinder the proper docking of the Pha with the bioreceptor, the procedure of Pha identification is essentially reduced to the treatment of a smaller number of simplest in structure most active and inactive compounds. A simple empirical scheme is suggested to estimate the APS numerically, while the contributions of different conformations of the same compound are taken into account by means of Boltzmann distribution. This enables us to make approximate quantitative predictions of activities. In application to rice blast activity we reached an approximately 100% (within experimental error) prediction probability of the activity qualitatively (yes, no), and with r (2) = 70% quantitatively.

Objective To assess the efficacy of latanoprost additive therapy in patients with intraocular pressure (IOP) out of control while taking maximum-tolerated medications and to determine whether pilocarpine therapy has a dose-dependent adverse effect on the efficacy of latanoprost therapy. Design Noncomparative case series. Participants Sixty-one eyes of 61 patients with chronic glaucoma with IOP out of control while receiving maximum-tolerated medications were treated with latanoprost additive therapy on a compassionate basis. Main outcome measures Follow-up was up to 22 months with a mean of 13.9 ± 5.7 months. Kaplan-Meier survival analysis with Mantel-Cox log-rank test was performed to determine the overall success of latanoprost additive therapy and to compare the success rates of high-dose pilocarpine, low-dose pilocarpine, and no pilocarpine therapies. The criterion for success was avoiding glaucoma surgery with IOP decrease of 20% or greater and final IOP less than 22 mmHg. The IOP change and its significance for patients satisfying and failing the criterion for success also were determined to assess the latanoprost additive therapy. In addition, a number of pretreatment variables, including pilocarpine therapy, were analyzed for a significant effect on the efficacy of latanoprost additive therapy using Cox proportional hazards regression analysis. Results Latanoprost additive therapy significantly lowered mean IOP by 3.9 ± 5.5 mmHg at 3 months and by 3.5 ± 5.8 mmHg at 12 months. The cumulative success rate of the latanoprost additive therapy was 70% at 1 month, 42% at 3 months, 40% at 6 months, and 30% at 12 months. Of the variables studied, only increased number of previous incisional glaucoma surgeries and IOP greater than 24 mmHg before latanoprost additive therapy were significant prognostic factors for failure of latanoprost additive therapy. Pilocarpine therapy in any dose had no significant effect. Conclusion This study supports a trial of latanoprost additive therapy before glaucoma surgery in patients with IOP out of control while receiving maximum-tolerated medications irrespective of pilocarpine therapy and the pilocarpine dosage, especially when the number of previous incisional glaucoma surgery is less than three and the IOP is less than 25 mmHg.

Following brief comments regarding the advantages of cell-based diversity algorithms and the selection of low-dimensional chemistry-space metrics needed to implement such algorithms, the notion of metric validation is discussed. Activity-seeded, structure-based clustering is presented as an ideal approach for the validation of either high- or low-dimensional chemistry-space metrics when validation by computer-graphic visualization is not possible. Whereas typical methods for reducing the dimensionality of chemistry-space inevitably discard potentially important information, we present a simple yet novel algorithm for reducing dimensionality by identifying which axes (metrics) convey information related to affinity for a given receptor and which axes can be safely discarded as being irrelevant to the given receptor. This algorithm often reveals a three- or two-dimensional subspace of a (typically six-dimensional) BCUT chemistry-space and, thus, enables computer graphic visualization of the actual coordinat...

In extension and improvement of previous results, a novel method is worked out for pharmacophore identification and activity prediction in structure-activity relationships. In this method, as in our previous works, each molecular system (conformation) of the training set is described by a matrix with both electron structural parameters (atomic charges, bond orders, etc.) and interatomic distances as matrix elements. This description includes a rather full geometry of charge and/or reactivity distribution thus providing a much better representation of the molecular properties in their interaction with the target. By multiple comparison of these matrices for the active and inactive compounds of the training set, a relatively small number of matrix elements are revealed that are common for all the active compounds and are not present in the same combination in the inactive ones. In this way a set of electronic and geometry parameters is obtained that characterize the pharmacophore (Pha). A major improvement of this scheme is reached by introducing the anti-pharmacophore shielding (APS) and a proper treatment of the conformational problem. The APS is defined as molecular groups and competing charges outside the basic skeleton (the Pha plus the inert neighbor atoms that do not affect the activity) that hinder the proper docking of the Pha with the bioreceptor thus diminishing (partially or completely) the activity. A simple empirical formula is derived to estimate the relative contribution of APS numerically. Two main issues are most affected by the APS: (1) the procedure of Pha identification is essentially simplified because only a small number of molecular systems with the highest activity and simplest structures (systems without APS) should be tried for this purpose; (2) with the APS known numerically, we can make a quantitative (or semiquantitative) prediction of relative activities. The contributions of different conformations (of the same molecular system) that possess the Pha and different APS is taken into account by means of a Boltzmann distribution at given temperatures. Applied to an example, rice blast activity, this approach proved to be rather robust and efficient. In validation of the method, the screening of 39 new compounds yields approximately 100% (within experimental error) prediction probability of the activity qualitatively (yes, no), and with r2=0.66 quantitatively.

We have previously shown that using agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in three-dimensional quantitative structure-activity relationship studies (3D-QSAR) presents a unique opportunity for accuracy and precision in measurement. Thus, a comparison of affinity's structural determinants for a set of compounds at two different recombinant dopamine receptors represents an attainable goal for 3D-QSAR. A molecular database of bound conformations of 16 structurally diverse agonists was established by alignment with a high-affinity template compound for the D1 receptor, 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-benzazepin. A second molecular database of the bound conformations of the same compounds was established against a second template for the D2 receptor, bromocriptine. These aligned structures suggested three-point pharmacophore maps (one cationic nitrogen and two electronegative centers) for the two dopamine receptors, which differed primarily in the height of the nitrogen above the plane of the catechol ring and in the nature of the hydrogen-bonding region. The ln(1/KL) values for the low-affinity agonist binding conformation at recombinant D1 and D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA (comparative molecular field analysis) of the 16 aligned structures. The resulting CoMFA models yielded cross-validated R2 (q2) values (standard error of prediction) of 0. 879 (1.471, with five principal components) and 0.834 (1.652, with five principal components) for D1 and D2 affinity, respectively. The simple R2 values (standard error of the estimate) were 0.994 (0.323) and 0.999 (0.116), respectively, for D1 and D2 receptor. F values were 341 and 2465 for D1 and D2 models, respectively, with 5 and 10 df. The predictive utility of the CoMFA model was evaluated at both receptors using the dopamine agonists, apomorphine and 7-OH-DPAT. Predictions of KL were accurate at both receptors. Flexible 3D searches of several chemical databases (NCI, MDDR, CMC, ACD, and Maybridge) were done using basic pharmacophore models at each receptor to determine the similarity of hit lists between the two models. The D1 and D2 models yielded different lists of lead compounds. Several of the lead compounds closely resembled high-affinity training set compounds. Finally, homology modeling of agonist binding to the D2 receptor revealed some consistencies and inconsistencies with the CoMFA-derived D2 model and provided a possible rationale for features of the D2 CoMFA contour map. Together these results suggest that CoMFA-homology based models may provide useful insights concerning differential agonist-receptor interactions at related receptors. The results also suggest that comparisons of CoMFA models for two structurally related receptors may be a fruitful approach for differential QSAR.

Objective The authors investigated the incidence of capsular opacification requiring YAG capsulotomy after primary trabeculectomy combined with phacoemulsification and implantation of all polymethylmethacrylate intraocular lenses. Design A prospective randomized study. Participants One hundred seventy-four eyes of 174 nonselected patients with primary open-angle glaucoma (POAG) were randomized to either no adjunctive mitomycin C (MMC) (control group of 93 eyes of 93 patients) or adjunctive subconjunctival MMC (MMC group of 81 eyes of 81 patients) during the primary glaucoma triple procedure (PGTP). Intervention Primary glaucoma triple procedure with and without MMC and YAG laser capsulotomy for posterior capsular opacification (PCO) was performed. Main outcome measures The incidences of YAG capsulotomy for PCO were compared between the control and MMC groups and also between the control group and the MMC subgroups (1 minute, 3 minutes, and 5 minutes of MMC application) using Kaplan-Meier analysis with Mantel-Cox log-rank test. Cox proportional hazard regression analysis also was performed to identify significant factors affecting capsular opacification. Results The control and MMC groups were similar in preoperative characteristics. However, the probability of PCO requiring YAG capsulotomy was significantly lower in the MMC group than in the control group ( P = 0.004). Among the MMC subgroups, MMC application for 3 minutes was most effective and significant when compared with that of the control group ( P = 0.002). Although not as significant as the intraoperative use of MMC ( P = 0.002), old age ( P = 0.026) and presence of diabetes mellitus ( P = 0.035) were also identified as significant beneficial factors for decreasing the incidence of YAG capsulotomy for PCO in Cox proportional hazard regression analysis. Conclusion Intraoperative subconjunctival MMC application during combined glaucoma and cataract surgery has a beneficial effect of inhibiting PCO after combined surgery in patients with POAG. Thus, after intraoperative subconjunctival application of MMC at the concentration of 0.5 mg/ml for 3 minutes, the aqueous MMC level must have been great enough to inhibit the lens epithelial cell proliferation to result in a long-term decrease in PCO.

OBJECTIVE: To characterize the informed consent process in routine, primary care office practice. DESIGN: Cross-sectional, descriptive evaluation of audiotaped encounters. SETTING: Offices of primary care physicians in Portland, Oregon. PARTICIPANTS: Internists (54%) and family physicians (46%), and their patients. MEASUREMENTS AND MAIN RESULTS: Audiotapes of primary care office visits from a previous study of doctor-patient communication were coded for the number and type of clinical decisions made. The discussion between doctor and patient was scored according to six criteria for informed decision making: description of the nature of the decision, discussion of alternatives, discussion of risks and benefits, discussion of related uncertainties, assessment of the patient's understanding and elicitation of the patient's preference. Discussions leading to decisions included fewer than two of the six described elements of informed decision making (mean 1.23, median 1.0), most frequent of these was description of the nature of the decision (83% of discussion). Discussion of risks and benefits was less frequent (9%), and assessment of understanding was rare (2%). Discussions of management decisions were generally more substantive than discussions of diagnostic decisions (p = .05). CONCLUSIONS: Discussions leading to clinical decisions in these primary care settings did not fulfill the criteria considered integral to informed decision making. Physicians frequently described the nature of the decision, less frequently discussed risks and benefits, and rarely assessed the patient's understanding of the decision.

Elderly persons are at risk for developing malnutrition due to a number of age-related factors, and conversely, malnutrition can worsen declining physiological and psychosocial conditions. The purpose of this study was to determine the nutritional status of an elderly, ambulatory outpatient population, and to evaluate change in nutritional status over a 2-year period. The 209 subjects were male veterans, over 65 years of age without acute disease-related nutritional risk factors. Nutrient intake was determined through food recalls and food frequency questionnaires. Anthropometrics included circumferences and skinfolds. Laboratory measures included selected minerals and vitamins, as well as hematological and lipid profiles. Mean intake of nutrients generally met or exceeded the Recommended Dietary Allowances with the exception of calories, although > 25% of subjects consumed inadequate amounts of thiamine, vitamin A, vitamin C, and calcium. Few subjects were found to be extremely underweight or obese, although skinfolds decreased over the two years. Mean laboratory measures were within normal range with the exception of selenium, cholesterol, and low density lipoprotein. Dietary, biochemical, and anthropometric data indicate good nutritional status in general, although dietary vitamin C, vitamin A, and calcium may be poor in subgroups; body fat as assessed by skinfolds appeared to decline; and selenium, lipid profiles, and hematological profiles warrant further investigation.

Determination of quantitative structure-activity relationship (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K(d)) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r(2)(q(2)) value of 0.829 and a simple r(2) = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K(d) values, the q(2) value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.

Patient autonomy is a guiding principle in medical decision-making in America. This is challenging when patients become mentally incapacitated and cannot express their preferences. Advance care planning (ACP) addresses this challenge. ACP is a deliberative and communicative process that helps people formulate and communicate preferences for future medical care in the event of mental incapacity. Advance directives are mechanisms for communicating and/or documenting ACP, and are either instructional (e.g. statement of treatment preferences in living wills) or proxy types (e.g. appointment of another person to speak on the patient's behalf). ACP discussions between patients and health care providers and patient-orientated educational ACP materials often ignore insights from 2 related activities, health promotion and human information processing. More effective ACP should occur with greater attention to the concepts of stages of change and self-efficacy, the Health Belief Model, and the necessary requisites for cognitive integration.

Author(s): Wallace, JI; Schwartz, RS; LaCroix, AZ; Uhlmann, RF; Pearlman, RA | Abstract: ObjectivesTo describe the incidence, anthropometric parameters, and clinical significance of weight loss in older outpatients.DesignFour-year prospective cohort study.SettingUniversity-affiliated Veterans Affairs Medical Center.PatientsTwo hundred forty-seven community-dwelling male veterans 65 years of age or older.MeasurementsAnthropometrics (weight, height, skin-folds, and circumferences), health status measures (Sickness Impact Profile scores, health care utilization, self-reported ratings of health), and bloodwork (cholesterol, albumin, others) were obtained at baseline and followed annually for 2 years. Outcome measures (hospitalization, nursing home placement, and mortality rates) were followed for a minimum of 2 years after any identified weight change.Main resultsThe mean annual percentage weight change for the study population was -0.5% (SD: +/- 4.0%; range: -17% to +25%). Four percent annual weight loss was determined to be the optimal cutpoint for defining clinically important involuntary weight loss using ROC curve analysis. The annual incidence of this degree of involuntary weight loss was 13.1%. At baseline, involuntary weight losers were similar to nonweight losers in age (73.9 +/- 7.9 vs 73.3 +/- 6.7 years), body mass index (26.8 +/- 3.9 vs 26.9 +/- 4.1 kg/m2), and all other anthropometric, health status, and laboratory measures. Relative to nonweight losers, involuntary weight losers had significantly (P l or = .05) greater decrements in central skinfold and circumference measures (subscapular skinfolds, -2.9 vs -0.4 mm; suprailiac skinfolds, -4.2 vs -0.2 mm; and waist to hip ratio, -.01 vs + .00). Both groups had significant decreases in their triceps skinfolds (an estimate of peripheral subcutaneous fat), whereas arm muscle area and albumin levels did not decline significantly in either group. Over a 2-year follow-up period, mortality rates were substantially higher (RR = 2.43; 95% CI = 1.34-4.41) among involuntary weight losers (28%) than among nonweight losers (11%). Of interest, a similar increase in 2-year mortality (36%) was also observed among subjects with voluntary weight loss (by dieting). Survival analyses adjusting for differences between weight losers and nonweight losers in baseline age, BMI, tobacco use, and other health status and laboratory measures yielded similar results.ConclusionsThese results indicate that involuntary weight loss occurred frequently (13.1% annual incidence) in this population of older veteran outpatients. When involuntary weight loss occurred, the predominant anthropometric changes were decrements in measures of centrally distributed fat (trunkal skinfolds and circumferences). Finally, involuntary weight loss greater than 4% of body weight appears to be clinically important as an independent predictor of increased mortality.

Previous research indicates that persons assigning values to ranges of health states consider some states to be worse than death. In a study of decisions regarding life-sustaining treat ments, the authors adapted and assessed existing methods for their ability to identify and quantify preferences for health states near to or worse than death in a population of well adults and nursing home residents. The cognitive burdens involved in these decisions were also evaluated. Hypothetical health states based on six attributes of functional status were constructed to describe severe constant pain, dementia, and coma. The methods of rank order, category scaling, time tradeoff, and standard gamble were adapted to quantify states worse than death. Cognitive burden was assessed using completion rates, interviewer as sessments, respondents' self-reporting, and investigators' evaluations. For both respondent groups, all methods showed similar degrees of cognitive burden for those able to complete the tasks and were similar in their ability to identify and quantify preferences. The majority of nursing home residents, however, were unable to complete or comprehend the mea surement tasks. Most respondents evaluated their current health and severe constant pain as better than death; dementia and coma were more often considered equal to or worse than death. These results indicate that respondents can and do evaluate some health states as worse than death. The authors recommend systematic inclusion of states worse than death to describe a more complete range of preference values and routine assessment of the cognitive burdens of assessment techniques to evaluate methodologies. Keywords: health status measurement; preference weights; utility measurement; health-state prefer ences; cognitive burden. (Med Decis Making 1994;14:9-18)

Empirical research pertaining to cardiopulmonary resuscitation (CPR), clinician behaviors related to do-not-resuscitate (DNR) orders and substituted judgment suggests potential contributions to medical ethics. Research quantifying the likelihood of surviving CPR points to the need for further philosophical analysis of the limitations of the patient autonomy in decision making, the nature and definition of medical futility, and the relationship between futility and professional standards. Research on DNR orders has identified barriers to the goal of patient involvement in these life and death discussions. The initial data on surrogate decision making also points to the need for a reexamination of the moral basis for substituted judgment, the moral authority of proxy decision making and the second-order status of the best interests standard. These examples of empirical research suggest that an interplay between empirical research, ethical analysis and policy development may represent a new form of interdisciplinary scholarship to improve clinical medicine.