The art and science of searching MEDLINE to answer clinical questions. Finding the right number of articles

The current medical environment makes information retrieval a matter of practical importance for clinicians. Many avenues present themselves to the clinician, but here we focus on MEDLINE by summarizing the current state of the art and providing an innovative approach for skill enhancement. Because new search engines appear rapidly, we focus on generic principles that can be easily adapted to various systems, even those not yet available. We propose an idealized classification system for the results of a MEDLINE search. Type A searches produce a few articles of high quality that are directly focused on the immediate question. Type B searches yield a large number of articles, some more relevant than others. Type C searches produce few or no articles, and those that are located are not germane. Providing that relevant, high-quality articles do exist, type B and C searches may often be improved with attention to search technique. Problems stem from poor recall and poor precision. The most daunting task lies in achieving the balance between too few and too many articles. By providing a theoretical framework and several practical examples, we prepare the searcher to overcome the following barriers: a) failure to begin with a well-built question; b) failure to use the Medical Subject Headings; c) failure to leverage the relationship between recall and precision; and d) failure to apply proper limits to the search. Thought and practice will increase the utility and enjoyment of searching MEDLINE

Low-Energy Nuclear Astrophysics - the Fascinating Region of A=7

We discuss results and future plans for low-energy reactions that play an important role in current nuclear astrophysics research and that happen to concentrate around the region of A=7. The 7Be(p,gamma)8B and the 3He(4He,gamma)7Be reactions are crucial for understanding the solar-neutrino oscillations phenomenon and the latter one plays a central role in the issue of cosmic 7Li abundance and Big-Bang Nucleosynthesis. We also present results regarding the host dependence of the half life of the electron-capture 7Be radio-nuclide.Comment: 8 pages, 6 figures. Proceedings of the Erice School on Nuclear Physics, 2006. To appear in: "Prog. Part. Nucl. Phys.

Molecular recording of mammalian embryogenesis.

Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes

FORCE-TJR: Innovative design for a national TJR comparative effectiveness research database

BACKGROUND: Joint replacement (TJR) registries have traditionnally focused on collecting implant data and analyzing time-to-revision. Sub-optimal outcomes short of revision are important to surgeons and patients. In 2010, the US federal Agency for Healthcare Research and Quality funded Function and Outcomes Research for Comparative Effectiveness in TJR (FORCE-TJR), a research consortium and database to collect comprehensive TJR outcomes, including patient-reported pain and function and post-operative sequelae. This $12 million research award will provide new information about post-TJR adverse events, patient-reported functional gain, and implant longevity. We developed novel methods to assure critical data collection and sustainability. METHODS: FORCE-TJR developed methods to (1) assemble a research consortium that includes a national sample of diverse surgeons and practices who agree to invite all patients to participate, (2) implement a virtual model for patient consent and data entry of consistent, validated patient-reported surveys, (3) conduct efficient screening for post-TJR sequelae and validated chart review and adjudication, and (4) document implant details. RESULTS: In the first 8 months, FORCE-TJR enrolled more than 90 surgeons in urban and rural settings, across 21 states; with academic, private, and HMO ownership; performing varied annual volumes of TJR surgery. Across practices, 80-95% of patients enrolled and more than 3250 patients consented to complete standardized surveys. More than 150 patients are enrolled each week, and enrollment rates will grow as additional surgeons join. CONCLUSION: FORCE-TJR employs innovative strategies to collect comprehensive post-TJR data from a national cohort of more than 30,000 patients. Comparative effectiveness research emerging from these data will include patient, implant, health system predictors of post-TJR adverse events, pain relief, functional gain, and revision. These TJR analyses will offer novel and important new evidence to guide patient and surgeon decisions, and are possible only because of this comprehensive research design

Using email reminders to engage physicians in an Internet-based CME intervention

BACKGROUND: Engaging practicing physicians in educational strategies that reinforce guideline adoption and improve the quality of healthcare may be difficult. Push technologies such as email offer new opportunities to engage physicians in online educational reinforcing strategies. The objectives are to investigate 1) the effectiveness of email announcements in engaging recruited community-based primary care physicians in an online guideline reinforcement strategy designed to promote Chlamydia screening, 2) the characteristics of physicians who respond to email announcements, as well as 3) how quickly and when they respond to email announcements. METHODS: Over a 45-week period, 445 recruited physicians received up to 33 email contacts announcing and reminding them of an online women's health guideline reinforcing CME activity. Participation was defined as physician log-on at least once to the website. Data were analyzed to determine participation, to compare characteristics of participants with recruited physicians who did not participate, and to determine at what point and when participants logged on. RESULTS: Of 445 recruited physicians with accurate email addresses, 47.2% logged on and completed at least one module. There were no significant differences by age, race, or specialty between participants and non-participants. Female physicians, US medical graduates and MDs had higher participation rates than male physicians, international medical graduates and DOs. Physicians with higher baseline screening rates were significantly more likely to log on to the course. The first 10 emails were the most effective in engaging community-based physicians to complete the intervention. Physicians were more likely to log on in the afternoon and evening and on Monday or Thursday. CONCLUSIONS: Email course reminders may enhance recruitment of physicians to interventions designed to reinforce guideline adoption; physicians' response to email reminders may vary by gender, degree, and country of medical training. Repetition of email communications contributes to physician online participation

Barriers to Health Care among the Elderly in Japan

Japan is undergoing a set of health care reforms aimed at cutting rising health care costs and increasing the efficiency of health care delivery. This empirical study used a large-scale community survey on 15,302 elderly people 65 years and older (56.0% women) conducted in seven municipalities in 2006, to reveal clear-cut evidence of barriers to necessary care. The reasons for not getting health care is attributed to health care cost for the elderly with lower income, while higher income counterparts reported being busy or having a condition not serious enough to seek care

Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens

Genetic screens help infer gene function in mammalian cells, but it has remained difficult to assay complex phenotypes—such as transcriptional profiles—at scale. Here, we develop Perturb-seq, combining single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-based perturbations to perform many such assays in a pool. We demonstrate Perturb-seq by analyzing 200,000 cells in immune cells and cell lines, focusing on transcription factors regulating the response of dendritic cells to lipopolysaccharide (LPS). Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions. We posit new functions for regulators of differentiation, the anti-viral response, and mitochondrial function during immune activation. By decomposing many high content measurements into the effects of perturbations, their interactions, and diverse cell metadata, Perturb-seq dramatically increases the scope of pooled genomic assays. Keywords: single-cell RNA-seq; pooled screen; CRISPR; epistasis; genetic interaction

Professional approaches in clinical judgements among senior and junior doctors: implications for medical education

<p>Abstract</p> <p>Background</p> <p>Clinical experience has traditionally been highly valued in medical education and clinical healthcare. On account of its multi-faceted nature, clinical experience is mostly difficult to articulate, and is mainly expressed in clinical situations as professional approaches. Due to retirement, hospitals in Scandinavia will soon face a substantial decrease in the number of senior specialist doctors, and it has been discussed whether healthcare will suffer an immense loss of experienced-based knowledge when this senior group leaves the organization. Both senior specialists and junior colleagues are often involved in clinical education, but the way in which these two groups vary in professional approaches and contributions to clinical education has not been so well described. Cognitive psychology has contributed to the understanding of how experience may influence professional approaches, but such studies have not included the effect of differences in position and responsibilities that junior and senior doctors hold in clinical healthcare. In the light of the discussion above, it is essential to describe the professional approaches of senior doctors in relation to those of their junior colleagues. This study therefore aims to describe and compare the professional approaches of junior and senior doctors when making clinical judgements.</p> <p>Methods</p> <p>Critical incident technique was used in interviews with nine senior doctors and nine junior doctors in internal medicine. The interviews were subjected to qualitative content analysis.</p> <p>Result</p> <p>Senior and junior doctors expressed a variety of professional approaches in clinical judgement as follows: use of theoretical knowledge, use of prior experience of cases and courses of events, use of ethical and moral values, meeting and communicating with the patient, focusing on available information, relying on their own ability, getting support and guidance from others and being directed by the organization.</p> <p>Conclusion</p> <p>The most prominent varieties of professional approaches were seen in use of knowledge and work-related experience. Senior doctors know how the organization has worked in the past and have acquired techniques with respect to long-term decisions and their consequences. Junior doctors, on the other hand, have developed techniques and expertise for making decisions based on a restricted amount of information, in relation to patients' wellbeing as well as organizational opportunities and constraints. This study contributes to medical education by elucidating the variation in professional approaches among junior and senior doctors, which can be used as a basis for discussion about clinical judgement, in both pre-clinical and clinical education. Further research is required to explain how these professional approaches are expressed and used in clinical education.</p

A Multiplexed Single-Cell CRISPR Screening Platform Enables Systematic Dissection of the Unfolded Protein Response

Functional genomics efforts face tradeoffs between number of perturbations examined and complexity of phenotypes measured. We bridge this gap with Perturb-seq, which combines droplet-based single-cell RNA-seq with a strategy for barcoding CRISPR-mediated perturbations, allowing many perturbations to be profiled in pooled format. We applied Perturb-seq to dissect the mammalian unfolded protein response (UPR) using single and combinatorial CRISPR perturbations. Two genome-scale CRISPR interference (CRISPRi) screens identified genes whose repression perturbs ER homeostasis. Subjecting ∼100 hits to Perturb-seq enabled high-precision functional clustering of genes. Single-cell analyses decoupled the three UPR branches, revealed bifurcated UPR branch activation among cells subject to the same perturbation, and uncovered differential activation of the branches across hits, including an isolated feedback loop between the translocon and IRE1α. These studies provide insight into how the three sensors of ER homeostasis monitor distinct types of stress and highlight the ability of Perturb-seq to dissect complex cellular responses.National Human Genome Research Institute (U.S.) (Grant P50HG006193