Identifying Diagnostic Studies in MEDLINE: Reducing the Number Needed to Read

Objectives. The search filters in PubMed have become a cornerstone in information retrieval in evidence-based practice. However, the filter for diagnostic studies is not fully satisfactory, because sensitive searches have low precision. The objective of this study was to construct and validate better search strategies to identify diagnostic articles recorded on MEDLINE with special emphasis on precision.Design. A comparative, retrospective analysis was conducted. Four medical journals were hand-searched for diagnostic studies published in 1989 and 1994. Four other journals were hand-searched for 1999. The three sets of studies identified were used as gold standards. A new search strategy was constructed and tested using the 1989-subset of studies and validated in both the 1994 and 1999 subsets. We identified candidate text words for search strategies using a word frequency analysis of the abstracts. According to the frequency of identified terms, searches were run for each term independently. The sensitivity, precision, and number needed to read (1/precision) of every candidate term were calculated. Terms with the highest sensitivity × precision product were used as free text terms in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” using the Boolean operator OR. In the 1994 and 1999 subsets, we performed head-to-head comparisons of the currently available PubMed filter with the one we developed.Measurements. The sensitivity, precision and the number needed to read (1/precision) were measured for different search filters.Results. The most frequently occurring three truncated terms (diagnos*; predict* and accura*) in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” produced a sensitivity of 98.1 percent (95% confidence interval: 89.9–99.9%) and a number needed to read of 8.3 (95% confidence interval: 6.7–11.3%). In direct comparisons of the new filter with the currently available one in PubMed using the 1994 and 1999 subsets, the new filter achieved better precision (12.0% versus 8.2% in 1994 and 5.0% versus 4.3% in 1999. The 95% confidence intervals for the differences range from 0.05% to 7.5% (p = 0.041) and –1.0% to 2.3% (p = 0.45), respectively). The new filter achieved slightly better sensitivities than the currently available one in both subsets, namely 98.1 and 96.1% (p = 0.32) versus 95.1 and 88.8% (p = 0.125).Conclusions. The quoted performance of the currently available filter for diagnostic studies in PubMed may be overstated. It appears that even single external validation may lead to over optimistic views of a filter’s performance. Precision appears to be more unstable than sensitivity. In terms of sensitivity, our filter for diagnostic studies performed slightly better than the currently available one and it performed better with regards to precision in the 1994 subset. Additional research is required to determine whether these improvements are beneficial to searches in practice.Biomedical databases are important sources of evidence in medical practice. However, information retrieval in such databases can become very time-consuming because searches that are likely to identify all relevant information also find many irrelevant articles.In recent years researchers have adopted various approaches in the development of search strategies to selectively retrieve different types of studies (therapy, prognosis, diagnosis and etiology) and different study designs.^1,2 Search strategies targeted at diagnostic studies have also been developed.^1,3–4 The most commonly used filter for diagnostic studies is almost certainly the one now publicly available in PubMed (Clinical Queries),⁵ which based on the work of Haynes and coworkers.¹ Their search filter with emphasis on sensitivity achieved a cross-validated mean sensitivity of approximately 87% combined with a (non–cross-validated) mean precision of approximately 8%.Compared with the filter for therapeutic studies, the diagnostic filter’s precision in particular is much lower. The main reason for this difference may be the inconsistent terminology used in diagnostic studies making them difficult to index and retrieve in electronic databases.In view of this high false-positive rate, we wondered if it would be possible to develop a more precise search strategy for selecting publications on diagnostic test evaluations without losing sensitivity. Our objective was to develop, test and validate a generic search strategy for the detection of diagnostic articles recorded on MEDLINE that can be applied in any diagnostic field in Medicine.     

Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols

Only three drugs are available for the treatment of East African trypanosomiasis. Patients suffer from painful application, severe side effects and increasing resistance against these drugs. Malaria tropica kills more than 2 million people every year mainly due to growing drug resistance. 4-Dialkylaminobicyclo[2.2.2]octan-2-ols and some of their esters have shown activity against both the causative organisms, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Ethers and new esters with markedly higher lipophilicity were prepared in three-step procedures from acyclic synthons. The new compounds were screened for their antiprotozoal activities against T. b. rhodesiense (STIB 900) and P. falciparum K1 (resistant to chloroquine and pyrimethamine), and for their cytotoxicity with l-6 cells by means of in vitro microplate assays. The results were compared to those of the parent compounds indicating that higher lipophilicity increases the antiprotozoal activities. The pivalate 10a showed the highest antitrypanosomal activity. The 4-chlorobenzoate 9b exhibited good antiplasmodial activity and low cytotoxicity. The most active antiplasmodial agent was the benzhydryl ether 13c which was nearly as active as chloroquine against sensitive strains.     

Imported strongyloidosis: a longitudinal analysis of 31 cases

BACKGROUND: Attention regarding imported tropical diseases is typically focused on malaria, although other parasitic diseases such as strongyloidosis may also cause serious health problems. The importance of assessing clinical features and of proper diagnosis and treatment is presented on the basis of 31 patients with imported strongyloidosis. METHODS: A retrospective analysis was performed regarding patients treated for strongyloidosis in two referral centers in Switzerland from 1998 to 2002. RESULTS: Imported strongyloidosis was investigated in 12 travelers and 19 immigrants. The reasons for diagnostic work-up were clinical symptoms in 84% and eosinophilia and screening in each of 22.5%. All patients had a history of travel or residence in endemic areas. Initial therapy was effective in 20 patients, and there was a tendency for a better response to ivermectin compared with the response to other drugs. A significant reduction in blood eosinophil count and serologic antibody titer was observed in patients responding to therapy after an average of 96 and 270 days, respectively. CONCLUSIONS: Strongyloidosis must be suspected in travelers and immigrants with skin or abdominal symptoms from regions where Strongyloides stercoralis is highly endemic. The results of this case series confirm that ivermectin is the drug of choice in treating imported strongyloidosis. Response to therapy can be assessed by serology and differential white blood count performed over 6 months after therapy.     

Positron-emission tomography imaging of early events after transplantation of islets of Langerhans

The aim of our study was to assess cell trafficking and early events after intraportal islet transplantation. Sprague-Dawley rat islets were incubated for various times, with various concentrations of 2-[F]fluoro-2deoxy-D-glucose (FDG), and in presence of various glucose concentrations. FDG-labeled syngeneic islets or FDG alone were injected in rats. Radioactivity was measured in the liver and in various organs by positron-emission tomography for 6 hours. FDG uptake increased with incubation time or FDG concentration and decreased in presence of glucose. In vivo, all islets implanted in the liver, with an uptake 4.4 times higher than controls (44.2% vs. 10.1%, P=0.02). Radioactivity in the liver decreased at the same rate after injection of labeled-islets and FDG alone. Ex vivo labeling of islets and imaging of posttransplant early events were feasible. Islets engrafted exclusively in the liver. No islet loss could be demonstrated 6 hours after transplantation.     

Image fusion analysis of 99mTc-HYNIC-Tyr3-octreotide SPECT and diagnostic CT using an immobilisation device with external markers in patients with endocrine tumours

Purpose The aim of this study was to assess the value of multimodality imaging using a novel repositioning device with external markers for fusion of single-photon emission computed tomography (SPECT) and computed tomography (CT) images. The additional benefit derived from this methodological approach was analysed in comparison with SPECT and diagnostic CT alone in terms of detection rate, reliability and anatomical assignment of abnormal findings with SPECT.Methods Fifty-three patients (30 males, 23 females) with known or suspected endocrine tumours were studied. Clinical indications for somatostatin receptor (SSTR) scintigraphy (SPECT/CT image fusion) included staging of newly diagnosed tumours (n=14) and detection of unknown primary tumour in the presence of clinical and/or biochemical suspicion of neuroendocrine malignancy (n=20). Follow-up studies after therapy were performed in 19 patients. A mean activity of 400 MBq of ^99mTc-EDDA/HYNIC-Tyr³-octreotide was given intravenously. SPECT using a dual-detector scintillation camera and diagnostic multi-detector CT were sequentially performed. To ensure reproducible positioning, patients were fixed in an individualised vacuum mattress with modality-specific external markers for co-registration. SPECT and CT data were initially interpreted separately and the fused images were interpreted jointly in consensus by nuclear medicine and diagnostic radiology physicians.Results SPECT was true-positive (TP) in 18 patients, true-negative (TN) in 16, false-negative (FN) in ten and false-positive (FP) in nine; CT was TP in 18 patients, TN in 21, FP in ten and FN in four. With image fusion (SPECT and CT), the scan result was TP in 27 patients (50.9%), TN in 25 patients (47.2%) and FN in one patient, this FN result being caused by multiple small liver metastases; sensitivity was 95% and specificity, 100%. The difference between SPECT and SPECT/CT was statistically as significant as the difference between CT and SPECT/CT image fusion (P<0.001). Twenty-seven abnormal SPECT findings in 17 patients could not be initially assigned to organs, but were clearly delineated after image fusion. In 21 patients (40%), clinically relevant information was obtained by image fusion as compared with SPECT alone.Conclusion Co-registration of SPECT and diagnostic CT using a cost-effective immobilisation device provides excellent accuracy for tumour detection of endocrine malignancies and is superior to SPECT and CT alone. Image fusion reduces false positive results and can detect additional lesions. Anatomical information provided by CT enables precise localisation of abnormalities observed in SPECT.     

Efficient induction of tumoricidal cytotoxic T lymphocytes by HLA-A0201 restricted, melanoma associated, L(27)Melan-A/MART-1(26-35) peptide encapsulated into virosomes in vitro

Cancer immunotherapy requires the induction of HLA class I restricted cytotoxic T lymphocytes (CTL) specific for tumor associated antigens (TAA). While a number of TAA have been identified, there is an urgent need for the development of adjuvants capable of stimulating CTL responsiveness. Previously, we reported the capacity of immunopotentiating reconstituted influenza virosomes (IRIV) to enhance CTL responses specific for synthetic peptides simultaneously added to cultures in soluble form. This effect was based on IRIV mediated activation of CD4(+) T cells. Here we investigated the "in vitro" immunogenicity of a novel virosome formulation coupling in a single reagent the adjuvant power of IRIV to the capacity of liposomes to efficiently encapsulate synthetic peptides. As a model epitope we chose L(27)Melan-A/Mart-1(26-35) HLA-A0201 restricted peptide from a melanoma-associated antigen widely used in tumor immunotherapy. The reagent thus developed induced the proliferation of CD4(+) T cells characterized by a T helper 1 cytokine profile and CXCR3 expression. Most importantly, it significantly enhanced the generation of L(27)Melan-A/Mart-1(26-35) specific CTL, as compared to soluble peptides, in particular at low nominal epitope concentrations (<1 microg/ml). These effector cells were able to efficiently kill HBL melanoma cells expressing Melan-A/MART-1 and HLA-A0201. The adjuvant effects observed were also detectable in the absence of CD4(+) T cells. Taken together our results suggest that this highly immunogenic antigenic formulation might qualify for clinical use in active, antigen-specific, melanoma immunotherapy.     

Pulmonary aspiration: new therapeutic approaches in the experimental model

BACKGROUND: Acute lung injury caused by gastric aspiration is a frequent occurrence in unconscious patients. Acute respiratory distress syndrome in association with gastric aspiration carries a mortality of up to 30% and accounts for up to 20% of deaths associated with anesthesia. Although the clinical condition is well known, knowledge about the exact inflammatory mechanisms is still incomplete. This study was performed to define the role of alveolar macrophages in this inflammatory response. In addition, potentially modifying effects of intratracheally applied nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate were investigated. METHODS: Rat alveolar macrophages were depleted by intratracheal administration of clodronate liposomes, and lung injury was evaluated 6 h after instillation of 0.1N hydrochloric acid. In a second set of experiments, pyrrolidine dithiocarbamate was intratracheally instilled 3 h after hydrochloric acid application, and injury parameters were determined. RESULTS: Depletion of alveolar macrophages resulted in decreased production of inflammatory mediators in acid aspiration (23-80% reduction of messenger RNA or protein of inflammatory mediators; P < 0.05) and consequently also in diminished neutrophil recruitment (36% fewer neutrophils; P < 0.01). Treatment with pyrrolidine dithiocarbamate was highly effective in decreasing neutrophil recruitment (66%; P < 0.01) and vascular permeability (80%; P < 0.001). CONCLUSIONS: These data suggest that alveolar macrophages play an essential role in the inflammatory response of acid-induced lung injury. For the first time, attenuation of acid-induced lung injury with an inhibitor, applied after the onset of injury, is shown.