HESI workshop summary: Interpretation of developmental and reproductive toxicity endpoints and the impact on data interpretation of adverse events.

The Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (HESI-DART) group held a hybrid in-person and virtual workshop in Washington, DC, in 2022. The workshop was entitled, "Interpretation of DART in Regulatory Contexts and Frameworks." There were 154 participants (37 in person and 117 virtual) across 9 countries. The purpose of the workshop was to capture key consensus approaches used to assess DART risks associated with chemical product exposure when a nonclinical finding is identified. The decision-making process for determining whether a DART endpoint is considered adverse is critical because the outcome may have downstream implications (e.g., increased animal usage, modifications to reproductive classification and pregnancy labeling, impact on enrollment in clinical trials and value chains). The workshop included a series of webinar modules to train and engage in discussions with federal and international regulators, clinicians, academic investigators, nongovernmental organizations, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART and new approach methodologies in the context of regulatory requirements and processes. Despite the differences in regulatory frameworks between the chemical and pharmaceutical sectors, the same foundational principles for data interpretation should be applied. The discussions led to the categorization of principles, which offer guidance for the systematic interpretation of data. Step 1 entails identifying any hazard by closely analyzing the data at the study endpoint level, while Step 2 involves assessing risk using weight of evidence. These guiding principles were derived from the collective outcomes of the workshop deliberations.

Scientific AI in Materials Science: a Path to a Sustainable and Scalable Paradigm.

Recently there has been an ever-increasing trend in the use of machine learning (ML) and artificial intelligence (AI) methods by the materials science, condensed matter physics, and chemistry communities. This perspective article identifies key scientific, technical, and social opportunities that the materials community must prioritize to consistently develop and leverage Scientific AI (SciAI) to provide a credible path towards the advancement of current materials-limited technologies. Here we highlight the intersections of these opportunities with a series of proposed paths forward. The opportunities are roughly sorted from scientific/technical (e.g. development of robust, physically meaningful multiscale material representations) to social (e.g. promoting an AI-ready workforce). The proposed paths forward range from developing new infrastructure and capabilities to deploying them in industry and academia. We provide a brief introduction to AI in materials science and engineering, followed by detailed discussions of each of the opportunities and paths forward.

Statistical Analysis of a Round-Robin Measurement Survey of Two Candidate Materials for a Seebeck Coefficient Standard Reference Material.

In an effort to develop a Standard Reference Material (SRM™) for Seebeck coefficient, we have conducted a round-robin measurement survey of two candidate materials-undoped Bi2Te3 and Constantan (55 % Cu and 45 % Ni alloy). Measurements were performed in two rounds by twelve laboratories involved in active thermoelectric research using a number of different commercial and custom-built measurement systems and techniques. In this paper we report the detailed statistical analyses on the interlaboratory measurement results and the statistical methodology for analysis of irregularly sampled measurement curves in the interlaboratory study setting. Based on these results, we have selected Bi2Te3 as the prototype standard material. Once available, this SRM will be useful for future interlaboratory data comparison and instrument calibrations.

The outcomes of pathway database computations depend on pathway ontology.

Different biological notions of pathways are used in different pathway databases. Those pathway ontologies significantly impact pathway computations. Computational users of pathway databases will obtain different results depending on the pathway ontology used by the databases they employ, and different pathway ontologies are preferable for different end uses. We explore differences in pathway ontologies by comparing the BioCyc and KEGG ontologies. The BioCyc ontology defines a pathway as a conserved, atomic module of the metabolic network of a single organism, i.e. often regulated as a unit, whose boundaries are defined at high-connectivity stable metabolites. KEGG pathways are on average 4.2 times larger than BioCyc pathways, and combine multiple biological processes from different organisms to produce a substrate-centered reaction mosaic. We compared KEGG and BioCyc pathways using genome context methods, which determine the functional relatedness of pairs of genes. For each method we employed, a pair of genes randomly selected from a BioCyc pathway is more likely to be related by that method than is a pair of genes randomly selected from a KEGG pathway, supporting the conclusion that the BioCyc pathway conceptualization is closer to a single conserved biological process than is that of KEGG.

Genome annotation errors in pathway databases due to semantic ambiguity in partial EC numbers.

We report on a new type of systematic annotation error in genome and pathway databases that results from the misinterpretation of partial Enzyme Commission (EC) numbers such as '1.1.1.-'. This error results in the assignment of genes annotated with a partial EC number to many or all biochemical reactions that are annotated with the same partial EC number. That inference is faulty because of the ambiguous nature of partial EC numbers. We have observed this type of error in multiple databases, including KEGG, VIMSS and IMG, all of which assign genes to KEGG pathways. The Escherichia coli subset of the KEGG database exhibits this error for 6.8% of its gene-reaction assignments. For example, KEGG contains 17 reactions that are annotated with EC 1.1.1.-. A group of three E.coli genes, b1580 [putative dehydrogenase, NAD(P)-binding, starvation-sensing protein], b3787 (UDP-N-acetyl-D-mannosaminuronic acid dehydrogenase) and b0207 (2,5-diketo-D-gluconate reductase B), is assigned to 15 of those reactions, despite experimental evidence indicating different single functions for two of the three genes. Furthermore, the databases (DBs) are internally inconsistent in that the description of gene functions for genes with partial EC numbers is inconsistent with the activities implied by reactions to which the genes were assigned. We infer that these inconsistencies result from the processing used to match gene products to reactions within KEGG's metabolic pathways. These errors affect scientists who use these DBs as online encyclopedias and they affect bioinformaticists who use these DBs to train and validate newly developed algorithms.

MCM-41 supported Cu-Mn catalysts for catalytic oxidation of toluene at low temperatures.

Complete catalytic oxidation of toluene was investigated on Cu-Mn doped mesoporous and microporous catalysts, i.e., Cu-Mn/MCM-41, Cu-Mn/beta-zeolite, Cu-Mn/ZSM-5 (where SiO2/Al2O3 is either 25 or 38), and Cu-Mn/porous silica, in the presence of excess oxygen. The result shows that mesoporous catalysts have exhibited the highest catalytic activity among these catalysts above. The less amount of coke formation due to the unique mesoporous structures could play a key role in the high activity on the mesoporous catalyst. In addition, the bimetallic Cu-Mn-MCM-41 supported catalyst shows higher oxidation activity than either single metal catalyst, i.e., Cu-MCM-41 and Mn-MCM-41. The highly dispersed Cu-Mn mixed oxides on mesoporous structures probably provide active sites for the complete oxidation of toluene on these mesoporous catalysts.

Effects of KI encapsulation in single-walled carbon nanotubes by Raman and optical absorption spectroscopy.

The effect of KI encapsulation in narrow (HiPCO) single-walled carbon nanotubes is studied via Raman spectroscopy and optical absorption. The analysis of the data explores the interplay between strain and structural modifications, bond-length changes, charge transfer, and electronic density of states. KI encapsulation appears to be consistent with both charge transfer and strain that shrink both the C-C bonds and the overall nanotube along the axial direction. The charge transfer in larger semiconducting nanotubes is low and comparable with some cases of electrochemical doping, while optical transitions between pairs of singularities of the density of states are quenched for narrow metallic nanotubes. Stronger changes in the density of states occur in some energy ranges and are attributed to polarization van der Waals interactions caused by the ionic encapsulate. Unlike doping with other species, such as atoms and small molecules, encapsulation of inorganic compounds via the molten-phase route provides stable effects due to maximal occupation of the nanotube inner space.

Thermal stability and reactivity of metal halide filled single-walled carbon nanotubes.

Thermal stability and reactivity to oxidation of several nanocomposite systems obtained by encapsulation of metal halides in single-walled carbon nanotubes are studied. Thermogravimetric analysis coupled with Raman spectroscopy allows insight into the various contributing factors, such as charge transfer, strain, and defect formation, and establishing a hierarchy of reactivity for the systems studied (AgX@SWCNTs, with X = Br, I; SWCNTs = arc discharge and HiPCO). The activation energy for oxidation decreases considerably after filling, indicating that filled nanotubes are more amenable to controlled modifications based on chemical reactivity than the originating empty nanotubes. The complete removal of the carbon shell at high temperatures does not preserve the nanowire morphology of the encapsulated halides; these are freed on surfaces in the form of nanoparticles arranged in 1D patterns. Metallic nanoparticles were obtained after hydrogen reduction of the halides, and growth of silicon nanowires in the footprint of the originating nanocomposites was demonstrated from such Co seeds. MX@SWCNTs (M = Ag, Co) can thus be used as environmentally stable nanoscale containers that allow the deliverance of catalytic nanoparticles in a prepatterned and aligned way.

Simultaneous atomic-resolution electron ptychography and Z-contrast imaging of light and heavy elements in complex nanostructures.

The aberration-corrected scanning transmission electron microscope (STEM) has emerged as a key tool for atomic resolution characterization of materials, allowing the use of imaging modes such as Z-contrast and spectroscopic mapping. The STEM has not been regarded as optimal for the phase-contrast imaging necessary for efficient imaging of light materials. Here, recent developments in fast electron detectors and data processing capability is shown to enable electron ptychography, to extend the capability of the STEM by allowing quantitative phase images to be formed simultaneously with incoherent signals. We demonstrate this capability as a practical tool for imaging complex structures containing light and heavy elements, and use it to solve the structure of a beam-sensitive carbon nanostructure. The contrast of the phase image contrast is maximized through the post-acquisition correction of lens aberrations. The compensation of defocus aberrations is also used for the measurement of three-dimensional sample information through post-acquisition optical sectioning.

An apparatus for spatially resolved, temperature dependent reflectance measurements for identifying thermochromism in combinatorial thin film libraries.

A metrology and data analysis protocol is described for high throughput determination of thermochromic metal-insulator phase diagrams for lightly substituted VO2 thin films. The technique exploits the abrupt change in near infrared optical properties, measured in reflection, as an indicator of the temperature- or impurity-driven metal-insulator transition. Transition metal impurities were introduced in a complementary combinatorial synthesis process for producing thin film libraries with the general composition space V(1-x-y)M(x)M'(y)O2, with M and M' being transition metals and x and y varying continuously across the library. The measurement apparatus acquires reflectance spectra in the visible or near infrared at arbitrarily many library locations, each with a unique film composition, at temperatures of 1 °C-85 °C. Data collection is rapid and automated; the measurement protocol is computer controlled to automate the collection of thousands of reflectance spectra, representing hundreds of film compositions at tens of different temperatures. A straightforward analysis algorithm is implemented to extract key information from the thousands of spectra such as near infrared thermochromic transition temperatures and regions of no thermochromic transition; similarly, reflectance to the visible spectrum generates key information for materials selection of smart window materials. The thermochromic transition for 160 unique compositions on a thin film library with the general formula V(1-x-y)M(x)M'(y)O2 can be measured and described in a single 20 h experiment. The resulting impurity composition-temperature phase diagrams will contribute to the understanding of metal-insulator transitions in doped VO2 systems and to the development of thermochromic smart windows.

Developmental regulation of steroidogenic enzyme gene expression in the periimplantation porcine conceptus: a paracrine role for insulin-like growth factor-I.

During periimplantation, the estrogen biosynthetic capability of the porcine conceptus is transient, coincident with morphological development (trophoblast elongation), and temporally associated with maximal uterine release of insulin-like growth factor-I (IGF-I) into the luminal fluid. We investigated the possible linkages of conceptus steroidogenesis and IGF-I by characterizing the developmental expression of the pig conceptus cytochrome P450 aromatase (P450arom) and cytochrome P450 17 alpha-hydroxylase (P45017 alpha) genes during periimplantation (days 8, 10, 12, 15, and 18) and the potential regulation by IGF-I of conceptus P450arom messenger RNA (mRNA) content. Primer pairs derived from porcine P450arom and P45017 alpha DNA sequences were used in reverse transcription-polymerase chain reaction analysis of conceptuses of differing morphologies and developmental stages. RNA transcripts for P450arom and P45017 alpha were readily detected only in conceptuses obtained at day 12 of pregnancy, with RNA levels varying according to morphological stage. P45017 alpha gene expression was maximal in spherical conceptuses greater than 5 mm in diameter, whereas P450arom mRNA was expressed in small (3-5 mm) and large (6-10 mm) spherical (large >> small), as well as day 12, filamentous conceptuses. Using primers derived from the human IGF-I receptor (IGF-IR) DNA sequence, constitutive expression of IGF-IR mRNA in porcine conceptuses throughout early pregnancy was demonstrated. Constitutively low expression of conceptus RNA transcripts for IGF-I ligand was similarly observed. However, uterine luminal fluid concentrations of IGF-I on day 12 were highly correlated with conceptus morphology, with maximal IGF-I in uteri possessing filamentous conceptuses. In vitro addition of IGF-I to day 12 conceptuses of filamentous or spherical morphologies resulted in distinct effects on P450arom mRNA abundance. Filamentous conceptuses had increased amounts of P450arom mRNA when treated with IGF-I. In contrast, IGF-I decreased the levels of P450arom mRNA in spherical conceptuses. IGF-I treatment did not alter mRNA expression of the IGF-IR gene in conceptuses of either morphology. These results demonstrate that transient expression of P450arom and P45017 alpha genes in perimplantation porcine conceptuses, document the constitutive expression of the conceptus IGF-IR gene, and support the involvement of endometrial IGF-I in modulation of embryonic P450arom mRNA abundance.

Molecular cloning of spermidine/spermine N1-acetyltransferase from the periimplantation porcine uterus by messenger ribonucleic acid differential display: temporal and conceptus-modulated gene expression.

Using messenger RNA (mRNA) differential display, we isolated several putative differentially expressed complementary DNAs (cDNAs) from the periimplantation (days 11-12) endometrium of unilaterally pregnant pigs. Nucleotide sequence analysis revealed that one cDNA clone was 87% homologous to human spermidine/ spermine N1-acetyltransferase (SSAT) over a stretch of 201 bp and represents the porcine homologue of this cDNA. A second differentially expressed cDNA encoded the porcine equivalent of the human fragile X mental retardation gene (FMR1), whereas a third specified an open reading frame with significant homology to the Escherichia coli N-acetylglucosamine transfer protein. Because SSAT is the rate-limiting enzyme in polyamine metabolism and polyamines are required cytosolic components for cell growth and differentiation, we characterized the expression of the porcine SSAT gene as a potential marker for endometrial growth and/or differentiation during early pregnancy. Further, using the consensus sequence from human and mouse cDNAs, PCR primers were designed and used to generate a 568-bp cDNA fragment from gravid endometrium that encompassed the entire open reading frame for porcine SSAT and which was subsequently used for Northern hybridization analysis. Two distinct SSAT transcripts, a major species of 1.3 kilobase pairs (kb) and a minor species of 3.5 kb were detected in endometrium, each with similar temporal patterns of expression. The levels of SSAT mRNA were higher (P = 0.03) in gravid than in nongravid uterine endometrium of unilaterally pregnant pigs on days 11-12. Similarly, SSAT mRNAs were more abundant (P = 0.0004) in day 12 pregnant than in day 12 cyclic, and in days 30, 60, 90, and 105 pregnant pig endometria. Uterine endometrial luminal epithelial (LE), glandular epithelial (GE), and stromal (ST) cells expressed the SSAT gene, but mRNA abundance varied among cell types (LE > GE > ST). Expression of SSAT gene in ovariectomized gilts treated with estrogen (E2, 100 microg/day), progesterone (P4, 200 mg/day) or E2 + P4 for 11 days was highest (P = 0.03) in the endometria of the P4 group. In contrast, E2 (10 nM), P4 (10 nM) and E2 + P4 had no effect on SSAT mRNA abundance in uterine endometrial explants from day 12 pregnant pigs. However, steady-state SSAT mRNA levels were induced in day 12 pregnant uterine explants by conditioned medium from day 12 filamentous but not spherical conceptuses. These data demonstrate that the temporal induction of the endometrial SSAT gene during periimplantation is modulated by a factor(s) secreted by the periimplantation conceptus and suggest that this enzyme may have an important role in uterine endometrial growth, remodeling and/or differentiation during periimplantation.

Cognitive functioning and posttraumatic stress disorder.

OBJECTIVE: The authors examined the association of cognitive impairment with posttraumatic stress disorder (PTSD) and other psychiatric diagnoses known to affect cognitive functioning. METHOD: The results of standardized neuropsychological tests were compared in four groups of Vietnam veterans: veterans with both a lifetime history of PTSD and a current diagnosis of depression, anxiety, or substance abuse; veterans with only a PTSD diagnosis; veterans with only a current diagnosis of depression, anxiety, or substance abuse; and veterans with none of these diagnoses. RESULTS: Veterans with both PTSD and concurrent diagnoses. exhibited more impairment in cognitive functioning than did veterans without these diagnoses. CONCLUSIONS: Cognitive deficits seen among persons diagnosed with PTSD may be associated with their concomitant diagnoses.

Residents' medical information needs in clinic: are they being met?

PURPOSE: Little is known about how often residents encounter unanswered clinical questions in their training. This knowledge would facilitate the development of curricula to help residents practice evidence-based medicine. This study was conducted to determine the frequency, characteristics, and pursuit of residents' clinical questions. SUBJECTS AND METHODS: Residents in a university-based primary care internal medicine program were observed in two hospital-based teaching clinics. Residents were interviewed after each patient encounter to determine whether they had any remaining clinical questions. At the end of each clinic session, they recorded their level of agreement with a series of statements about factors that were expected to motivate residents to seek the answers to each question. One week later, residents were contacted to determine if they had pursued these questions. RESULTS: Sixty-four residents were interviewed after 401 (99%) of 404 patient encounters. They identified 280 new questions, approximately 2 questions for every 3 patients. The most common types of questions were related to therapy (38%) or diagnosis (27%). The residents were subsequently contacted about 277 (99%) of their questions. Of these, only 80 (29%) were pursued, most commonly by consulting textbooks (31%), original articles (21%), or attending physicians (17%). In a multivariable analysis, belief that the patient expected the answer (odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.3 to 4.0, P = 0.004) and fear of malpractice exposure (OR = 2.1, 95% CI: 1.0 to 4.3, P = 0.05) were associated with information pursuit. Lack of time (60%) and forgetting the question (29%) were the most frequent reasons for failing to pursue a question. CONCLUSION: Residents frequently encountered new clinical questions in the outpatient clinic, but infrequently answered them. Efforts to demonstrate the feasibility of timely searches, remind them of their questions, and reinforce the exigency (educational if not clinical) of all questions may reclaim missed opportunities for self-directed learning.

Metabolic activation of olefins. Conversion of 1-octene to a putative reactive intermediate 1-octen-3-one: an alternative pathway to epoxidation.

The enzymic activation of a model olefin oct-1-ene was studied in rat liver microsomal systems in vitro. An active metabolite was trapped using N-acetylcysteine and identified by means of capillary GLC/mass spectrometry and 360 MHz 1H NMR as S-3-oxo-octyl-N-acetylcysteine. A two step pathway for the formation of this adduct was proposed involving first the production of oct-1-en-3-ol by NADPH dependent mixed function oxidases and secondly a NADP or NAD linked oxidation, independent of cytochrome P-450, to yield the putative reactive intermediate oct-1-en-3-one. Under physiological conditions, oct-1-en-3-one, prepared chemically, reacted non-enzymically with N-acetylcysteine with a t1/2 of about 6 sec. Enzymes catalysing the NADP-dependent oxidation of octen-3-ol were present in microsomal preparations from a number of organs apart from the liver, those from adrenal and intestinal epithelia showing the next highest levels of activity. Unlike the activation of octene, rates of hepatic activation of octen-3-ol were not induced by pretreatment of rats with phenobarbitone or 3-methylcholanthrene. Using 1-octene as the substrate, comparisons were made of alternative routes of hepatic metabolism activation. Relative to the rate of formation of the 3-oxo intermediate trapped with N-acetylcysteine, epoxidation of octene and subsequent hydrolysis to octane-1,2-diol was over 40 times more rapid. The rate of formation of a presumptive oxirane precursor trapped with the haem of cytochrome P-450 as N-(2-hydroxyoctyl)protoporphyrin IX was about 17-fold lower.

Pregnancy-dependent expression of leukaemia inhibitory factor (LIF), LIF receptor-beta and interleukin-6 (IL-6) messenger ribonucleic acids in the porcine female reproductive tract.

Leukaemia inhibitory factor (LIF) and interleukin-6 (IL-6) are candidate embryo-maternal signalling molecules which are present within the uterine luminal micro-environment. We examined the relative expression of the mRNAs encoding LIF and IL-6, as well as the LIF-binding subunit (LIFR-beta) of the LIF receptor and, as a potential downstream cytokine-responsive gene, beta(2)-microglobulin (beta(2)m), in porcine peri-implantation conceptuses, and in placenta and endometrium during early and mid-pregnancy. Peri-implantation spherical and filamentous conceptuses expressed LIFR-beta and beta(2)m mRNAs with no LIF mRNA present. Rapid development in days 11/12 spherical conceptuses to the filamentous stage was accompanied by transiently increased IL-6 gene expression. The corresponding endometrium, in contrast, expressed LIF in addition to these other mRNAs. LIFR-beta, IL-6 and beta(2)m, but not LIF mRNAs, were expressed in the Jag-1 cell line, an in vitro model for porcine day 14 trophoblast. The greatest steady-state amounts of LIF, LIFR-beta and IL-6 mRNAs in both the endometrium and placenta were evident at the post-implantation stages (days 30 and 60>day 18 of pregnancy). Treatment of porcine endometrial explants with human recombinant (hr)LIF or hrIL-6 resulted in no change in, or diminished, the presence of endometrial beta(2)m mRNA, respectively. Addition of LIF to peri-implantation conceptus explant cultures, in contrast, induced beta(2)m mRNA synthesis. These results highlight the potential importance of both the endometrium and placenta as sources, as well as targets, of these cytokines throughout pregnancy. Cytokine modulation of beta(2)m, a known in vitro mitogen, may constitute one mechanism for local control of trophoblast and endometrial proliferation.

The unique endometrial expression and genomic organization of the porcine IGFBP-2 gene.

The insulin-like growth factor-binding proteins (IGFBPs-1-6) modulate the mitogenic and differentiative actions of the IGFs and may have IGF-independent functions. This study examined the gene expression and pregnancy-regulation of the IGF/IGFBP system in porcine uterine endometrium and myometrium during the periimplantation period and later stages of pregnancy. Endometrial IGFBP-2 mRNA abundance exhibited stage of pregnancy-dependent induction; whereas little or no IGFBP-2 mRNA was found in myometrium. IGFBP-2 protein was immunolocalized to the endometrial glandular and luminal epithelia (staining on day 60 > day 12) with minimal or no immunostaining of uterine stroma observed. IGFBP-3 and IGFBP-4 transcript levels became elevated in endometrium after implantation; whereas, IGFBP-5 and IGFBP-6 mRNAs were in greater abundance in periimplantation than post-implantation endometrium. IGFBP-1 transcripts, in contrast, could not be identified in porcine endometrium or myometrium of pregnancy. As a pre-requisite to understanding the pregnancy-induction and endometrial-specificity of the uterine-expressed IGFBP-2 gene, cosmids encompassing the pig IGFBP-2 chromosomal locus were isolated and characterized. This gene is comprised of four exons that span > 29 kb and encode a 316 amino acid precursor protein. All four exons were found to be G/C rich with exon 1 and immediate 5' flank exhibiting hallmarks of a CpG island. This latter region was devoid of TATA and CAAT motifs. Results identify the preferential endometrial expression of different IGFBP genes at either the periimplantation or post-implantation periods, perhaps reflecting distinct actions of these proteins at the embryo-maternal and feto-maternal interfaces, respectively. Interactions of steroid receptors, endometrial transcription factors and their corresponding cis elements may confer the unique uterine expression of the IGFBP-2 gene.

Graduate medical education training in clinical epidemiology, critical appraisal, and evidence-based medicine: a critical review of curricula.

PURPOSE: To systematically review the published literature on graduate medical education (GME) curricula in clinical epidemiology, critical appraisal, and evidence-based medicine (EBM). METHOD: The author searched the Medline and Educational Resources Information Center (ERIC) databases from 1973 through 1998, and also searched the references of the captured papers. The author reviewed all peer-reviewed reports of GME curricula (with or without effectiveness studies) in critical appraisal, clinical epidemiology, or evidence-based medicine, extracting objectives, formats, and evaluations (including effectiveness, process, and satisfaction). For effectiveness evaluations, he also identified the outcomes, outcome measures, methodologic characteristics, and results. RESULTS: The search produced 18 reports. The most common objective of the curricula described in the reports was improving critical skills; the most common format was resident-directed small-group seminar. The most common outcome-evaluation measure was a multiple-choice examination. Only seven of the reports evaluated the curricula's effectiveness, and only four met a minimum methodologic standard of a pretest-posttest controlled trial. The impacts on critical appraisal skills of the curricula in those four reports ranged from no effect to a 23% net absolute increase in test scores. CONCLUSION: These reports provide useful guides for medical educators, but many suffered from incomplete descriptions and inadequate evaluations of their curricula. The curricula themselves often focused on critical appraisal to the exclusion of other EBM skills and had limited effectiveness. In addition to increased methodologic rigor, future studies should focus on more meaningful outcome evaluations. Curricula should use residents' actual clinical experiences and teach EBM skills in real time in existing clinical and educational venues.

Selective self-stereotyping.

In an examination of group members' responses to the threat of negative in-group characterizations, sorority/fraternity members were asked to rate themselves, their own sorority/fraternity, sororities/ fraternities in general, and students in general on attributes that were stereotypic of sororities/ fraternities. Results showed that individuals selectively self-stereotyped-they embraced positive stereotypes as highly descriptive of themselves and their closest in-groups but rejected negative stereotypes. They did not, however, deny that negative stereotypes were accurate or valid-they continued to accept them as typical of sororities/fraternities in general. This represents a protective, creative response to the threat posed by exposure to negative group attributes, in which self-stereotyping as a result of self-categorization is selective rather than complete.

Is experience a good teacher? How interns and attending physicians understand patients' choices for end-of-life care. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

BACKGROUND: Recent studies have shown that physicians do not accurately assess patients' health status or treatment preferences. Little is known, however, about how physicians' levels of training or experience relate to their abilities to assess these preferences. To better understand this phenomenon, the authors compared the abilities of medical interns and attending physicians to predict the choices of their adult patients for end-of-life care. METHODS: 230 seriously-ill adult inpatients were surveyed about their desires for cardiopulmonary resuscitation, their current quality of life, and their attitudes toward six other common adverse outcomes. The medical intern and attending physician who cared for these patients were asked to estimate the patient's responses for all of the same items. Agreement was assessed using the kappa statistic. RESULTS: Compared with interns, attending physicians had known patients longer, had talked with patients more frequently about prognosis, and felt they knew more about their patients' preferences (all p < .0001). Despite this, the attending physicians were no more accurate than the interns in assessing patients' preferences. Both interns and attending physicians had only a fair understanding of patients' preferences for cardiopulmonary resuscitation or their quality of life (kappa statistics 0.32 to 0.47), and even less understanding of their willingness to tolerate adverse outcomes (kappa statistics -0.03 to 0.37). CONCLUSIONS: For this cohort of seriously ill patients, neither medical interns nor their attending physicians were consistently accurate in assessing patients' preferences, and attending physicians were not more accurate than medical interns. Attending physicians should not assume that they can infer patients' preferences any better than the interns caring for these hospitalized patients.