AMEE Guide No. 123 - How to read studies of educational costs.

Healthcare and health professions education share many of the same problems in decision making. In both cases, there is a finite amount of resources, and so choices need to be made between alternatives. To navigate the options available requires effective decision making. Choosing one option requires consideration of its opportunity cost - the benefit forgone of the other competing options. The purpose of this abridged AMEE guide is to introduce educational decision-makers to the economic concept of cost, and how to read studies about educational costs to inform effective cost-conscious decision-making. This guide leads with a brief review of study designs commonly utilized in this field of research, followed by an overview of how study findings are commonly presented. The tutorial will then offer a four-step model for appraising and considering the results of an economic evaluation. It asks the questions: (1) Can I trust the results? (2) What are the results telling me? (3) Could the results be transferred to my context? (4) Should I change my practice?

Invited article: development of high-field superconducting Ioffe magnetic traps.

We describe the design, construction, and performance of three generations of superconducting Ioffe magnetic traps. The first two are low current traps, built from four racetrack shaped quadrupole coils and two solenoid assemblies. Coils are wet wound with multifilament NbTi superconducting wires embedded in epoxy matrices. The magnet bore diameters are 51 and 105 mm with identical trap depths of 1.0 T at their operating currents and at 4.2 K. A third trap uses a high current accelerator-type quadrupole magnet and two low current solenoids. This trap has a bore diameter of 140 mm and tested trap depth of 2.8 T. Both low current traps show signs of excessive training. The high current hybrid trap, on the other hand, exhibits good training behavior and is amenable to quench protection.

Search for a Neutron Electric Dipole Moment.

The possible existence of a nonzero electric dipole moment (EDM) of the neutron is of great fundamental interest in itself and directly impacts our understanding of the nature of electro-weak and strong interactions. The experimental search for this moment has the potential to reveal new sources of T and CP violation and to challenge calculations that propose extensions to the Standard Model. The goal of the current experiment is to significantly improve the measurement sensitivity to the neutron EDM over what is reported in the literature. The experiment has the potential to either measure the magnitude of the neutron EDM or to lower the current experimental limit by two orders of magnitude. Achieving these objectives will have a major impact on our understanding of the physics of both weak and strong interactions.

Determination of the Neutron Lifetime Using Magnetically Trapped Neutrons.

We report progress on an experiment to measure the neutron lifetime using magnetically trapped neutrons. Neutrons are loaded into a 1.1 T deep superconducting Ioffe-type trap by scattering 0.89 nm neutrons in isotopically pure superfluid (4)He. Neutron decays are detected in real time using the scintillation light produced in the helium by the beta-decay electrons. The measured trap lifetime at a helium temperature of 300 mK and with no ameliorative magnetic ramping is substantially shorter than the free neutron lifetime. This is attributed to the presence of neutrons with energies higher than the magnetic potential of the trap. Magnetic field ramping is implemented to eliminate these neutrons, resulting in an [Formula: see text] trap lifetime, consistent with the currently accepted value of the free neutron lifetime.

Neutron-detected tomography of impurity-seeded superfluid helium.

We describe a neutron radiography technique that can be used to map the distribution of 3He impurities in liquid 4He, providing direct and quantitative access to underlying transport processes. Images reflecting finite normal- and superfluid-component 4He velocity fields are presented.

Valpha gene replacement in a TCRalpha knock-in mouse.

Using a TCRalpha chain knock-in mouse, we demonstrate that V-gene replacement can operate in the T cell receptor alpha locus. Functional TCRalpha chain transcripts generated by Valpha-gene replacement at the site of the Valpha-embedded heptamer were identified in splenic T cells. This finding shows that Valpha-gene replacement can likely be used to shape the peripheral T cell repertoire. The conservation of the embedded heptamer in most Valpha segments adds support to the notion that V-gene replacement is a mechanism maintained to diversify the immune system and that argues that it is common to B and T cells.

Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial.

Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients > 55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment.

Laparoscopic repositioning of a ventriculo-peritoneal catheter tip for a sterile abdominal cerebrospinal fluid (CSF) pseudocyst.

Abdominal cerebrospinal fluid (CSF) pseudocyst is an uncommon but well-described complication that is reported to occur in <1% of ventriculo-peritoneal (VP) shunts. Management options for pseudocysts include various types of shunt revisions, which recently have been conducted laparoscopically. We report the case of an 11-year-old girl in whom a sterile abdominal CSF pseudocyst was successfully fenestrated and the VP catheter repositioned using laparoscopy. This technique in the setting of a noninfected pseudocyst has proven to be safe, with results comparable to the conventional open technique. However, the long-term success rate is still unknown.

VH gene replacement in thymocytes.

The quasi-monoclonal (QM) mouse has a functionally rearranged H chain gene inserted into its natural position in the IgH locus. In this position, the H chain gene is subject to many of the same activities as normally arranged H chain genes, including somatic hypermutation, V(H) gene replacement, and class switch recombination. Here, we have used this mouse strain to determine some of the rules that govern the V(D)J recombination activity of the IgH locus in thymus. We focused on the requirements for V(H) gene replacement. In normal mice, thymic DJ(H) rearrangements are common, but VDJ(H) rearrangements are not. We found intermediate products of V(H) replacement in double-positive CD4(+)CD8(+) cells of the QM thymus, demonstrating that the inserted V(H) gene was accessible and ruling out the possibility that a V(H) gene per se cannot be rearranged in the thymus. We found transcripts from the knocked-in H chain gene of QM, but no mu H chain protein was detectable in thymocytes. Cloning and sequencing of these transcripts revealed that some had been generated by V(H) gene replacement. Corresponding signal joints could also be identified. These results suggest that neither a B cell-specific signal nor an Ig protein are necessary to activate V(H)-to-VDJ(H) joining in thymocytes. Possible mechanisms remaining to account for overcoming the barrier to V(H) joining in thymocytes include the insertion of a transcriptionally active gene segment and/or the inactivation of a silencer.

Bilateral eventration of the diaphragm with perforated gastric volvulus in an adolescent.

Bilateral congenital eventration of the diaphragm almost uniformly presents in infancy with respiratory compromise and is associated with a high mortality rate. Delayed presentation of diaphragmatic eventration in older children and adults may be associated with acute gastric volvulus. Thus, any patient with abdominal pain, vomiting, or nonspecific gastrointestinal symptoms in association with abnormal diaphragmatic findings on chest x-ray should undergo further diagnostic workup with upper gastrointestinal series or computed tomography (CT) scan. Treatment of gastric volvulus requires immediate surgical repair to prevent subsequent necrosis and perforation. The authors describe a case report of bilateral congenital diaphragmatic eventration complicated by a perforated gastric volvulus in a 13-year-old boy. Emergent reduction of the volvulus, closure of the perforated stomach, plication of the diaphragm, and placement of gastrostomy was performed successfully.

Same-session endoscopic retrograde cholangiopancreatography and cholecystectomy.

The objective was to determine the efficacy and safety of same-session endoscopic retrograde cholangiopancreatography (ERCP) and cholecystectomy. Twenty-two patients who had ERCP and cholecystectomy performed in the same session under one general anesthetic were compared with 77 patients who had ERCP followed by surgery in the ensuing days. In the 93 patients who underwent attempted laparoscopic cholecystectomy, there was no difference in conversion to open rates between the same-session group and the delayed group. The length of stay after ERCP was longer in the delayed group. Same-session ERCP and cholecystectomy is safe and efficacious, and its routine use should be considered.

Evolution of the recombination signal sequences in the Ig heavy-chain variable region locus of mammals.

The Ig and T cell receptor (TCR) loci have an exceptionally dynamic evolutionary history, but the mechanisms responsible remain a subject of speculation. Ig and TCR genes are unique in vertebrates in that they are assembled from V, D, and J segments by site-specific recombination in developing lymphocytes. Here we examine the extent to which the V(D)J recombination in germline cells may have been responsible for remodeling Ig and TCR loci in mammals by asking whether gene segments have evolved as a unit, or whether, instead, recombination signal sequences (RSSs) and coding sequences have different phylogenies. Four distinct types of RSS have been defined in the human Ig heavy-chain variable region (Vh) locus, namely H1, H2, H3, and H5, and no other RSS type has been detected in other mammalian species. There is a well-supported discrepancy between the evolutionary history of the RSSs as compared with the Vh coding sequences: the RSS type H2 of one Vh gene segment has clearly become replaced by a RSS type H3 during mammalian evolution, between 115 and 65 million years ago. Two general models might explain the RSS swap: the first involves an unequal crossing over, and the second implicates germline activation of V(D)J recombination. The Vh-H2/RSS-H3 recombination product has likely been selected during the evolution of mammals because it provides better V(D)J recombination efficiency.

Specific antibody production by V(H)-gene replacement.

V(H)-gene replacement is a recombination event in which a pre-existing immunoglobulin heavy chain gene can be altered by the replacement of the rearranged V(H) gene segment with another V(H) gene segment. Although this event has been demonstrated in various model systems, its role in generating antibody diversity is still unsettled. We have used a genetically modified mouse strain, QM, with a quasi monoclonal primary B cell repertoire specific for NP to determine whether V(H) gene replacement can generate a new antigen specificity. Hybridomas generated from QM splenocytes after immunization with different antigens, gave rise to antibodies with specificity to the immunizing antigen or with new specificities. We found V(H)-gene replacement was used to change the original heavy chain gene rearrangement specific for NP into a heavy chain gene encoding the new antigen specificity. V(H)-gene replacement intermediates were detected both before and after the immunization, suggesting that the event was selective rather than instructive. These results demonstrate that V(H)-gene replacement can generate a new antibody heavy chain gene with a different functional and selectable antigen specificity.

The potential for treatment of idiopathic thrombocytopenic purpura with anti-D to prevent splenectomy: a predictive cost analysis.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults that can be manifested by severe bleeding episodes. Adult ITP patients have a low rate of spontaneous remission, and symptomatic patients commonly undergo splenectomy; however, maintenance therapy may increase the rate of remission, allowing splenectomy to be avoided. Anti-D is a recently licensed treatment for ITP that has the potential to delay, and possibly avoid, the need for splenectomy. We used preliminary data from an ongoing clinical trial to evaluate the costs involved in using anti-D therapy for 1 year with the intent of avoiding the need for splenectomy. We accounted for different possible outcomes at the completion of the clinical trial. An economic model with a theoretical cohort of 100 patients was developed using the model of an ongoing clinical trial. The average wholesale price was used to determine the cost of an infusion of anti-D based on an average dose ($1,213 per infusion). The cost of splenectomy was determined by a literature review ($16,000). Costs were calculated for all known patient outcomes; where outcomes were unknown and likely to vary, all possible outcomes were accounted for (splenectomy or no splenectomy). In our theoretical cohort, 31 of 100 patients were taken off anti-D and received splenectomy, 32 of 100 were stable after receiving anti-D and would not need splenectomy, and 37 of 100 had Indeterminate outcomes after receiving anti-D. When compared with the cost of the hypothetical scenario of initially giving all 100 patients splenectomy ($1.6 million), a minimum of 47 patients would have to avoid splenectomy to result in a cost savings for our cohort of 100 patients. The group of 47 patients avoiding splenectomy would be composed of the 32 patients comprising the stable group and at least 15 of the 37 patients comprising the group with indeterminate outcomes. If all 37 of the patients in the group with indeterminate outcomes avoid splenectomy, $363,000 and 69 spleens would be saved. Our data suggest that in the phase III trial of maintenance anti-D therapy versus immediate splenectomy, anti-D therapy will be a cost-effective option if 47% or more of patients avoid splenectomy.

Magnetic trapping of neutrons

Accurate measurement of the lifetime of the neutron (which is unstable to beta decay) is important for understanding the weak nuclear force and the creation of matter during the Big Bang. Previous measurements of the neutron lifetime have mainly been limited by certain systematic errors; however, these could in principle be avoided by performing measurements on neutrons stored in a magnetic trap. Neutral-particle and charged-particle traps are widely used for studying both composite and elementary particles, because they allow long interaction times and isolation of particles from perturbing environments. Here we report the magnetic trapping of neutrons. The trapping region is filled with superfluid 4He, which is used to load neutrons into the trap and as a scintillator to detect their decay. Neutrons in the trap have a lifetime of 750(+330)(-200) seconds, mainly limited by their beta decay rather than trap losses. Our experiment verifies theoretical predictions regarding the loading process and magnetic trapping of neutrons. Further refinement of this method should lead to improved precision in the neutron lifetime measurement.

Evolutionarily conserved and divergent expression of members of the FGF receptor family among vertebrate embryos, as revealed by FGFR expression patterns in Xenopus.

Fibroblast growth factors (FGFs) mediate many cell-cell signaling events during early development. While the actions of FGFs have been well-studied, the roles played by specific members of the FGF receptor (FGFR) family are poorly understood. To characterize the roles played by individual FGFRs we compared the regulation and expression of the three Xenopus FGFRs described to date (XFGFR-1, XFGFR-2, and XFGFR-4). First, we describe the expression of Xenopus FGFR-4; XFGFR-4 is present as a maternal mRNA and is found in the embryo through at least the tadpole stage. XFGFR-4 and XFGFR-1 mRNAs are present at comparable levels, arguing that both mediate FGF signaling during early development. Second, the expression of XFGFR-4 in animal caps differs from the expression of XFGFR-1 and XFGFR-2, suggesting that the FGFRs are independently regulated in ectoderm. Third, using whole-mount in situ hybridization, we show that XFGFR-1, XFGFR-2, and XFGFR-4 are expressed in dramatically different patterns, arguing that specific FGF signaling events are mediated by different members of the FGFR family. Among these, FGF signaling during the induction of neural crest cells is likely to be mediated by XFGFR-4. Comparison of our results with previously reported FGFR expression patterns reveals that FGFR-1 expression is highly conserved among vertebrate embryos, and FGFR-2 expression shows many features that are conserved and some that are divergent. In contrast, the expression pattern of FGFR-4 is highly divergent among vertebrate embryos.

Malignant transformation of an ovarian mature cystic teratoma presenting as a rectal mass.

BACKGROUND: Squamous cell carcinoma arising from malignant degeneration of a mature cystic teratoma is rare with a reported incidence of approximately 1-3%. The most common presenting symptoms are lower abdominal pain and increasing abdominal girth of several months' duration. Approximately 50% of the patients present with FIGO stage I while 35-38% present with stage III diseases. CASE: The case described herein represents an unusual presentation and initial diagnostic dilemma of locally aggressive squamous cell carcinoma arising in an ovarian dermoid cyst, with invasion into the distal rectum and anal canal causing rectal bleeding similar to the presentation of anal squamous cell carcinoma. Despite aggressive surgical management with posterior exenteration and optimal tumor debulking followed by 5040-cGy pelvic radiation utilizing 25-MV photons, the patient developed pelvic recurrence at the vaginal cuff 6 weeks after completion of her adjuvant radiotherapy. She subsequently failed cis-platinum single-agent chemotherapy and died 9 months after her initial surgery and diagnosis. CONCLUSION: Squamous cell carcinoma in the anal canal, diagnosed by colonoscopy or proctoscopy, could be an unusual presentation of that arising from malignant degeneration of an ovarian dermoid cyst. This tumor may behave in a locally aggressive manner and be resistant to pelvic radiation or single-agent chemotherapy of cis-platinum. The current experience of adjuvant treatment after comprehensive staging and cytoreductive surgery reported in the world literature is limited, and the optimal management of the malignancy remains unclear.

Interpretive reproducibility of stress Tc-99m sestamibi tomographic myocardial perfusion imaging.

BACKGROUND: Observer variability has been shown with interpretation of planar thallium-201 images. The interpretive reproducibility of technetium-99m sestamibi tomographic imaging is unknown. This study evaluated the interpretive reproducibility of interpretable Tc-99m sestamibi tomographic images among nuclear cardiologists with a wide range of training and experience. METHODS: Three experienced readers (EX) and 3 less-experienced readers (LEX) interpreted 138 exercise and rest Tc-99m sestamibi tomographic images (101 were abnormal in patients with coronary artery disease [CAD], 37 were normal in patients with <5% likelihood of CAD) twice in random sequence without clinical data. Images of good to excellent quality were randomly selected from a database at 2 nuclear cardiology laboratories. Intraobserver and interobserver agreement for global, left anterior descending (LAD) territory, non-LAD first (normal/abnormal) and second (normal/fixed/reversible) order, and defect extent (normal/single-vessel CAD/multi-vessel CAD) were assessed with percent agreement and Cohen's kappa (kappa) statistic. RESULTS: With regard to intraobserver agreement, first and second order ranged from 87% to 94% and 80% to 90% for global, 82% to 96% and 78% to 95% for LAD, and 88% to 91% and 80% to 90% for non-LAD, respectively. Defect extent ranged from 75% to 90%. There were no differences between EX and LEX for global and non-LAD first and second order, LAD first order, and defect extent. LAD second order was 93% for EX compared with 88% (P = .015) for LEX. With regard to interobserver agreement, first and second order ranged from 73% to 89% and 64% to 85% for global, 73% to 93% and 69% to 91% for LAD, and 76% to 88% and 68% to 84% for non-LAD, respectively. Defect extent ranged from 61% to 82%. Global first and second order ranged from 85% to 87% and 78% to 82% for EX compared with 73% to 84% and 64% to 79% for LEX. LAD first and second order ranged from 89% to 91% and 88% to 89% for EX compared with 73% to 91% and 69% to 70% for LEX. Non-LAD first and second order ranged from 82% to 86% and 76% to 77% for EX compared with 76% to 86% and 68% to 81% for LEX. Defect extent ranged from 69% to 75% for EX compared with 59% to 77% for LEX. CONCLUSIONS: There is moderate to excellent interpretive reproducibility with stress Tc-99m sestamibi SPECT imaging among nuclear cardiologists with a wide range of training and experience.