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Izhodišča: Test QuantiFERON TB (QFT TB) je prvenstveno namenjen za odkrivanje latentne (LTBI) okužbe z bacili tuberkuloze (TB). Članek obsega retrospektivno analizo rezultatov testa QFT TB v Sloveniji med letoma 2008 in 2019, opozarja na vplive predanalitskih dejavnikov na rezultate testa ter govori o razlogih za nastanek nejasnih rezultatov in o občutljivosti testa pri bolnikih z aktivno obliko TB. Metode: V obdobju 2008–2019 smo v Laboratoriju za mikobakterije Klinike Golnik s testom QFT TB testirali 29.352 vzorcev krvi bolnikov iz različnih zdravstvenih ustanov v Sloveniji. Na rezultatih testa QFT TB smo izvedli retrospektivno analizo. Rezultati: Delež pozitivnih rezultatov testa QFT TB se z leti postopno znižuje. V letu 2008 je znašal 20,8 %, v letu 2019 pa 10,7 %, kar pomeni, da je v zadnjih dvanajstih letih upadel za 48,6 %. Največjo težavo predstavljajo nejasni rezultati (letno povprečno 4,3 %), saj so za zdravnika nepovedni. Občutljivost testa QFT TB pri bolnikih z aktivno obliko TB je 82,9 %, kar je primerljivo s podatki iz tujine. Zaključek: Pomembno je, da pri odvzemu in pošiljanju krvi dosledno sledimo navodilom, saj je test QFT TB zelo občutljiv na predanalitske dejavnike in klinično stanje preiskovancev. Delež pozitivnih rezultatov testa QFT TB z leti pospešeno upada, kar je povezano z napori za omejitev širjenja TB in upadom primerov aktivne TB v naši državi. Background: The QuantiFERON TB (QFT TB) test is primarily intended to detect latent (LTBI) tuberculosis (TB) infections. This work is based on a retrospective analysis of QFT TB test results in Slovenia between 2008 and 2019. It also draws attention to the influence of pre-analytical factors on a test result, on reasons that lead to indeterminate results, and on the sensitivity of the test in patients with active tuberculosis (TB). Methods: Between 2008 and 2019, we performed the QFT TB test in Laboratory for Mycobacteria of the University Clinic Golnik on 29,352 blood samples of patients from various health care institutions in Slovenia. A retrospective analysis was performed on QFT TB test results. Results: The proportion of positive QFT TB test results is gradually decreasing. In 2008, the proportion was 20.8% and in 2019, it declined to 10.7%, meaning that it has decreased by 48.6% in the last 12 years. The biggest problem are indeterminate results (on average 4.3% per year), as they are unpredictive to a physician. The sensitivity of the QFT TB test in patients with active TB is 82.9%, which is comparable to the data from abroad. Conclusion: The QFT TB test is highly sensitive to pre-analytical factors and the clinical condition of subjects therefore it is crucial that we follow instructions regarding blood taking and dispatching. The proportion of positive QFT TB test results has been rapidly declining over the years, which is a consequence of efforts to limit the spread of active TB in our country.

Pemphigus is an autoimmune dermatological condition that affects dogs and has in its clinical aspects a similarity to leishmaniasis, in which a differential diagnosis by means of histopathological examination is necessary. The present study sought to report a case of a dog, male, mixed breed, 10 years old, diagnosed with pemphigus and, later, diagnosed with leishmaniosis. Upon diagnosis, the animal presented only a lesion in the nasal plane, without apathy and without systemic changes, as evidenced by hematological and biochemical tests. After performing histopathological examination, the animal was diagnosed with pemphigus and underwent immunosuppressive treatment, obtaining significant improvement of the lesion. Under clinical suspicion of leishmaniasis, the animal was subjected to serological exams RIFI and ELISA resulting in an indeterminate result in ELISA and 1/40 reagent in the RIFI. As this is not a very relevant result, it was decided to perform another histopathological examination of the lesion where the presence of Leishmania spp. In this new exam it was not possible to obtain a diagnosis of pemphigus again, since the animal was under immunosuppressive treatment. Therefore, it is concluded that, in cases of co-infection of autoimmune diseases, such as pemphigus and canine leishmaniasis, the differential diagnosis by means of histopathological examination is extremely relevant to the patient's therapeutic success and prognosis. Thus, it is necessary to note that the diagnosis of pemphigus does not exclude the diagnosis of leishmaniosis.

Context.—Immunohistochemical expression of mismatch repair (MMR) protein is a well-accepted method for routine screening for Lynch syndrome with relatively high sensitivity and specificity. Occasionally, however, immunohistochemistry (IHC) can yield an equivocal result with poor reproducibility and the potential for misdiagnosis.Objective.—To determine the frequency and significance of indeterminate MMR IHC expression in patients routinely screened for Lynch syndrome and correlation with germline mutation studies.Design.—Semiquantitative scoring of MMR IHC was performed by image analysis in 479 cases, of which 380 were colorectal and 99 endometrial cancer. Scores of 10% or more, less than 10%, and 0% were used as cutoffs for retained, indeterminate, and loss of expression, respectively. Negative and indeterminate IHC results were confirmed by mutational studies.Results.—Four hundred eighteen of 479 cases (87.2%) were reported as retained expression, 45 (9.3%) as loss of expression, and 16 (3.3%) as indeterminate expression. Fifteen of 45 (33.3%) and 8 of 16 (50%) with loss and indeterminate expression, respectively, were found to have Lynch syndrome by germline studies. The overall frequency of Lynch syndrome in our patient population was 4.8% (23 of 479), and 34.7% of these (8 of 23) were associated with indeterminate IHC expression. In the indeterminate group, MLH1 germline mutation was the most frequent (6 of 13; 46.2%), followed by MSH6 (4 of 13; 30.7%).Conclusions.—Our findings provide further evidence that indeterminate IHC should be further investigated for possible MMR germline mutation. Guidelines for interpretation of MMR IHC and the establishment of more objective criteria for defining indeterminate results are important to improve the sensitivity and specificity of the IHC assay.

Both the QuantiFERON-TB Gold Plus (QFT-Plus) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) tests are interferon gamma (IFN-γ) release assays (IGRAs) intended to detect in vitro cell-mediated immune responses to Mycobacterium tuberculosis antigens. In this study, we retrospectively analyzed performance data for both the QFT-GIT and QFT-Plus test systems from over 2 million samples. QFT-Plus and QFT-GIT testing was performed as specified in the respective package inserts at 23 Quest Diagnostics sites. Blood specimens were collected from individuals in all 50 states from November 2018 through December 2019. Retrospective analyses compared the proportion of positive, indeterminate, and conversion/reversion results. The overall proportion of QFT-positive results was 7% for both the QFT-Plus and QFT-GIT. The proportion of positive results was highest for QFT-GIT (7.5%) followed by the heparin 1-tube QFT-Plus (7.2%); a lower proportion of positives was observed with the 4-tube (all four QFT tubes were used in blood collection) QFT-Plus (6.0%). The proportions of indeterminate results for the 1-tube (heparin-only tube collection) and 4-tube QFT-Plus methods were less than 1% and 4%, respectively. This study indicates a higher proportion of positive results for M. tuberculosis than data from other studies. Additionally, the proportion of indeterminate QFT results were markedly lower when the sample was transported in one lithium-heparin tube instead of direct inoculation into 4 QFT-Plus tubes at the site of blood collection. IMPORTANCE In this study, we retrospectively analyzed results from both the QFT-GIT and QFT-Plus test systems from over 2 million blood specimens. The variables analyzed were (i) QFT positivity rates among various U.S. populations, (ii) indeterminate rates among various types of blood draws and how often an indeterminate result was resolved within 30 days after the initial draw, and (iii) the association of TB1 and TB2 antigen tubes with IGRA reversion and conversion events from serial QFT testing. This is, to our knowledge, the largest QFT study representing patients from an extensive geographic coverage across the United States and U.S. territories.

LamPORE is a novel diagnostic platform for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA combining loop-mediated isothermal amplification with nanopore sequencing, which could potentially be used to analyze thousands of samples per day on a single instrument. We evaluated the performance of LamPORE against reverse transcriptase PCR (RT-PCR) using RNA extracted from spiked respiratory samples and stored nose and throat swabs collected at two UK hospitals. The limit of detection of LamPORE was 10 genome copies/μl of extracted RNA, which is above the limit achievable by RT-PCR, but was not associated with a significant reduction of sensitivity in clinical samples. Positive clinical specimens came mostly from patients with acute symptomatic infection, and among them, LamPORE had a diagnostic sensitivity of 99.1% (226/228; 95% confidence interval [CI], 96.9% to 99.9%). Among negative clinical specimens, including 153 with other respiratory pathogens detected, LamPORE had a diagnostic specificity of 99.6% (278/279; 98.0% to 100.0%). Overall, 1.4% (7/514; 0.5% to 2.9%) of samples produced an indeterminate result on first testing, and repeat LamPORE testing on the same RNA extract had a reproducibility of 96.8% (478/494; 94.8% to 98.1%). LamPORE has a similar performance as RT-PCR for the diagnosis of SARS-CoV-2 infection in symptomatic patients and offers a promising approach to high-throughput testing.

Malignant pleural effusion (MPE) is diagnosed by the presence of malignant cells in the pleural fluid or a pleural biopsy. The presence of MPE is classified as M1a in the 8th edition of the tumor-node-metastasis staging for lung cancer (1). Therefore, the diagnosis of MPE is important for disease staging and establishing a treatment plan in lung cancer patients. Thoracentesis is the first step in diagnosing MPE; however, its reported sensitivity varies from 40% to 87% (2,3). A pleural biopsy may be necessary in cases where the pleural fluid cytology shows a negative or indeterminate result. When pleural thickening or nodularity are noted on contrast-enhanced computed tomography (CT) images, an image-guided percutaneous pleural biopsy is recommended as the standard diagnostic method (4,5). However, these disease-related abnormalities on the pleura are not always observed on chest CT scans, and the pleural biopsy can result in false negatives.

INTRODUCTION: With the emergence of multidrug resistant Gram-negative bugs, there is an urgent need for rapid detection of these resistant organisms. AIM: This study was performed to assess the utility of a novel chromogenic medium in the detection of carbapenemase producing Enterobacteriaceae from various clinical specimens. MATERIALS AND METHODS: A total of 202 isolates of Enterobacteriaceae, which were resistant to meropenem (10 μg) disc by standard disc diffusion method, were analyzed over a period of 6 months. These isolates were subjected to the modified Hodge test (MHT) and inoculated onto the chromogenic medium. Following which the results were analyzed. RESULTS: It was observed that 76.73% of the Enterobacteriaceae gave a positive result on the MHT, 18.31% were negative and 4.95% gave indeterminate result. While 88.11% produced growth on the chromogenic medium, 6.93% yielded no growth and 4.95% gave variable results. Concordance in the results of the two tests was found to be 65.34%. CONCLUSION: Enterobacteriaceae are emerging to be carbapenem resistant and are responsible for the soaring rates of Healthcare Associated Infections (HAIs), especially among critically ill patients. Hence, early detection of the same is important in controlling HAIs.

Background Debate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts the screening outcome (test result and lung cancer risk) of the final screening round. Methods 15â €..792 participants were randomised (1:1) of which 7900 randomised into a screening group. CT screening took place at baseline, and after 1, 2 and 2.5â €..years. Initially, three screening outcomes were possible: negative, indeterminate or positive scan result. Probability for screening outcome in the fourth round was calculated for subgroups of participants. Results Based on results of the first three rounds, three subgroups were identified: (1) those with exclusively negative results (n=3856; 73.0%); (2) those with ≥1 indeterminate result, but never a positive result (n=1342; 25.5%); and (3) with ≥1 positive result (n=81; 1.5%). Group 1 had the highest probability for having a negative scan result in round 4 (97.2% vs 94.8% and 90.1%, respectively, p

The problem of the two couriers is an old introductory problem from basic algebra first described by Augustus de Morgan in 1828 in his algebra textbook. The two couriers problem is interesting in that three of the possible answers are interrelated: zero, infinity, and undefined or indeterminate result. These three results relate to division from fractions; and more specifically, infinity and undefined or indeterminate result from division by zero. The aspect of division by zero makes the two couriers problem an ideal one for independent, objective examination within the mathematical framework of transmathematics—where division by zero is defined and has specific mathematical properties. The application to the original problem of the two couriers using transmathematics provides further insight into the answers of infinity, and undefined or indeterminate result, and a contradistinction between the answers provided in conventional mathematics versus transmathematics.

Compared to its predecessor QuantiFERON-TB Gold In Tube (QFT-IT), QuantiFERON-TB Gold Plus (QFT-Plus) contains an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T cells. The ability to discriminate CD4+ and CD8+ responses is suggested to be useful in differentiating stages of Mycobacterium tuberculosis infection. While QFT-Plus has already been evaluated in adults, there are not enough data in children evaluated for suspected active tuberculosis (TB) or latent TB infection (LTBI). A prospective cross-sectional study was conducted among children aged 0 to 17 years who were evaluated for suspected active TB or screened for LTBI. All children underwent QFT-Plus and further clinical, radiological, and/or microbiological analyses according to clinical scenario. Of the 198 children enrolled, 43 (21.7%) were tested because of suspicion of active TB. A total of 12/43 (27.9%) were diagnosed with active TB, and among these, 10/12 (83.3%) had a positive QFT-Plus assay. Of the 155 children screened for LTBI, 18 (11.6%) had a positive QFT-Plus, and 5 (2.5%) had an indeterminate result. TB1 and TB2 quantitative responses were not able to discriminate active disease from latent infection. The percent agreement between TB1 and TB2 was 100%. QFT-Plus assay showed good sensitivity for active TB and was particularly useful for the evaluation of children with suspected LTBI, giving a low rate of indeterminate results in this group. More studies are needed to properly evaluate QFT-Plus ability in discriminating active disease from latent infection.

To fulfil the World Health Organization (WHO) End TB strategy, screening for tuberculosis (TB) in immigrants is an important component of the strategy to reduce the TB burden in low-incidence countries. Oman has an annual TB incidence rate of 5.7 per 100000 and transmission from migrants with activated latent TB infection (LTBI) to nationals is a concern. The aim of this study was to determine the proportion of migrants to the Sultanate of Oman with LTBI. The study used an interferon-gamma release assay (IGRA) to assess previous exposure to TB, defining LTBI and a positive IGRA with a normal chest X-ray. 1049 subjects were surveyed. Six participants were excluded from the analysis as they had been recently vaccinated and 1 had an indeterminate result, thus 1042 subjects were included. The overall IGRA-positive rate was 22.4% (234/1042), 30.9% and 21.2% of African and Asian migrants, respectively, were IGRA-positive. Fifty-eight of the participants had a strong IGRA reactivity defined as more than 4 IU/ml. The study shows the proportion of migrants from Asia and Africa with LTBI and 24.7% (58/234) of IGRA-positive migrants had an IGRA of >4 IU/ml, defining a subpopulation with a high risk of developing active TB in the first two years of arrival to the country.

BACKGROUND: To minimize false-positive diagnoses of HIV in exposed infants, the World Health Organization (WHO) recommends confirmatory testing for all infants initiating antiretroviral therapy (ART). In settings where confirmatory testing is not feasible or intermittently performed, clinical decisions may be aided by semi-quantitative cycle thresholds (Cts) that identify positive results most likely to be false-positive. METHODS: We developed a decision analysis model of HIV-exposed infants in sub-Saharan Africa to estimate the clinical consequences of deferring ART for infants with weakly positive (“indeterminate”) results.” We assessed the degree to which “indeterminate” results might reduce the number of infants starting ART unnecessarily while missing a small number of HIV-infected infants. Our primary outcome was the ratio of averted unnecessary ART regimens to additional HIV-related deaths (due to false-negative diagnosis) at different Ct cutoffs. RESULTS: The clinical consequences of adopting an indeterminate range varied with the prevalence of HIV and Ct cutoff. Considering a Ct cutoff of ≥33, adopting an indeterminate range could prevent a median of 1.4 infants from receiving ART unnecessarily (95% UR: 1.0–2.0) for each additional HIV-related death. This ratio could be improved by prioritizing infants with indeterminate results for confirmatory testing [median 8.8 (95% UR: 6.0–13.3)] and by adopting a higher cutoff [median 82.3 (95% UR: 49.0–155.8) with Ct ≥36]. CONCLUSIONS: When implemented in settings where confirmatory testing is not universal, the benefits of classifying weakly positive results as “indeterminate” may outweigh the risks. Accordingly, the WHO has recommended Ct values ≥33 be considered indeterminate for infant HIV diagnosis.

OBJECTIVES: To investigate the performance of the meropenem and imipenem double-ended Etest ± EDTA and the tablet-based (meropenem and meropenem + dipicolinic acid) KPC/MBL Confirm Kit to detect cfiA metallo-β-lactamase (MBL) in Bacteroides fragilis.METHODS: Well-characterized B. fragilis isolates, most from previously published studies, harbouring the cfiA gene and covering a wide range of meropenem MICs were included (n = 21).RESULTS: The imipenem double-ended Etest showed an indeterminate result in 95% of the included isolates with the cfiA gene (20 of 21), whereas the meropenem double-ended Etest gave an MIC ratio ≥8 (positive test) with all the isolates. All isolates that were meropenem intermediate or resistant had a zone diameter difference ≥6 mm with the KPC/MBL Confirm Kit.CONCLUSIONS: The meropenem double-ended Etest and not imipenem should be preferred for phenotypic detection of MBLs in B. fragilis. The KPC/MBL Confirm Kit could be an alternative with isolates that are meropenem intermediate or resistant (MIC >2 mg/L).

In this work, we validated raw results of the new version of Xpert MTB/RIF, Xpert Ultra, and found that unique combinations of Ultra probe and melting temperature shift (ΔTm) can discriminate between rifampicin-resistance (RR) conferring rpoB mutations and identify specific RR mutations including disputed mutations commonly missed in rapid phenotypic drug susceptibility tests. Negative ΔTm was associated with all mutations except those in codon 450. The combination of ΔTm values with the capturing probes enabled to differentiate mutations in codons 428, 430, 431, 432, 434, 435, 441, 445, 446, and 452, including disputed mutations. Mutation Asp435Tyr was unambiguously distinguished from Asp435Val through probe rpoB2 |ΔTm|, while mutations Ser441Gln and Ser441Leu were discriminated from the rest by |ΔTm| values of probes rpoB2 and rpoB3. Mutations His445Asp and His445Tyr were distinguished from disputed mutations His445Leu and His445Asn through probe rpoB3 |ΔTm|. Ser450Leu was distinguished from Ser450Trp by probe rpoB4A |ΔTm| except for one strain with an outlier rpoB4A Tm of 70.9°C in contrast to the other 13 strains with rpoB4A Tm of 73.3-73.8°C. The indeterminate result associated with His445Arg may be caused by its |ΔTm|=1.8°C compared with |ΔTm| typically exceeding 2°C for other mutations. With these findings, we propose potential full utilization of Ultra results for RR tuberculosis (RR-TB) surveillance in association with the growing number of digitally linked Xpert MTB/RIF machines in more than half of high TB burden countries worldwide. Our findings may guide end-users to rapidly identify underlying RR mutations that will flag the national TB control program to investigate suspected cases of RR-TB transmission based on epidemiologic linking. This, in turn, may rule-out transmission between RR-TB patients in a specific setting. Discriminatory results of Ultra could also distinguish relapse from reinfection, and resolve discordance between an RR Ultra result and a low-level RS phenotypic result due to a disputed mutation.

In this work, we validated raw results of the new version of Xpert MTB/RIF, Xpert Ultra, and found that unique combinations of Ultra probe and melting temperature shift (ΔTm) can discriminate between rifampicin-resistance (RR) conferring rpoB mutations and identify specific RR mutations including disputed mutations commonly missed in rapid phenotypic drug susceptibility tests. Negative ΔTm was associated with all mutations except those in codon 450. The combination of ΔTm values with the capturing probes enabled to differentiate mutations in codons 428, 430, 431, 432, 434, 435, 441, 445, 446, and 452, including disputed mutations. Mutation Asp435Tyr was unambiguously distinguished from Asp435Val through probe rpoB2 |ΔTm|, while mutations Ser441Gln and Ser441Leu were discriminated from the rest by |ΔTm| values of probes rpoB2 and rpoB3. Mutations His445Asp and His445Tyr were distinguished from disputed mutations His445Leu and His445Asn through probe rpoB3 |ΔTm|. Ser450Leu was distinguished from Ser450Trp by probe rpoB4A |ΔTm| except for one strain with an outlier rpoB4A Tm of 70.9°C in contrast to the other 13 strains with rpoB4A Tm of 73.3-73.8°C. The indeterminate result associated with His445Arg may be caused by its |ΔTm|=1.8°C compared with |ΔTm| typically exceeding 2°C for other mutations. With these findings, we propose potential full utilization of Ultra results for RR tuberculosis (RR-TB) surveillance in association with the growing number of digitally linked Xpert MTB/RIF machines in more than half of high TB burden countries worldwide. Our findings may guide end-users to rapidly identify underlying RR mutations that will flag the national TB control program to investigate suspected cases of RR-TB transmission based on epidemiologic linking. This, in turn, may rule-out transmission between RR-TB patients in a specific setting. Discriminatory results of Ultra could also distinguish relapse from reinfection, and resolve discordance between an RR Ultra result and a low-level RS phenotypic result due to a disputed mutation.

International audience; OBJECTIVE:We conducted a parallel evaluation of the diagnostic accuracy of VIKIA® Rota-Adeno, a rapid diagnostic test (RDT) and Premier™ Rotaclone® an enzyme immunoassay (EIA) using reverse transcription polymerase chain reaction (RT-PCR) as the reference standard. The study was part of a rotavirus surveillance project in Niger.RESULTS:The sensitivity of both tests was 80.7%. After exclusion of one indeterminate result by visual reading, the specificity of the Premier™ Rotaclone® was 100% by visual or optical density readings and that of VIKIA® Rota-Adeno test was 95.5%. Inter-reader agreement was excellent for both tests (kappa = 1). Our results showed almost similar performance of the EIA and RDT when compared to RT-PCR. Hence, the VIKIA® Rota-Adeno could be a good alternative for use in peripheral health centres where laboratory capacity is limited.

Aims: The usefulness of rapid oral fluid HIV antibody tests has rarely been evaluated in exposed babies. Study Design: A diagnostic survey comparing the performance of oral fluid HIV antibody test and the routine rapid blood screening test. Place and Duration of Study: University College Hospital, Ibadan and Nigerian Institute of Medical Research, Lagos, between May 2010 and April 2011. Methodology: The study involved children aged less than 18 months referred for screening in two large HIV care programmes in Nigeria using rapid antibody tests - an oral fluid test (Test A) and the routine blood test (Test B). The testing was blinded and HIV status was confirmed using DNA PCR. Results: A total of 94 children were studied with ages ranging from 0.13 to less than 18months. Out of the 94 parallel tests, when compared with DNA PCR, there were 7 (7.5%) discordant results. Test A gave one false positive, one false negative and no indeterminate result. Test B gave four false positive, one false negative and two indeterminate results. Test A had a sensitivity of 93.3%, specificity of 98.7%, positive

We investigated the diagnostic value of the BRAF(V600E) mutation of thyroid nodules according to ultrasonography (US) features and the time of BRAF(V600E) mutation analysis.A total of 304 nodules in 295 patients (mean age, 49.4 years) were included. Thyroid nodules were classified as suspicious or probably benign on US. Group 1 (n = 168) included nodules with BRAF(V600E) mutation analysis at the time of the initial US-guided fine needle aspiration biopsy (US-FNAB) and group 2 (n = 136) included nodules with analysis at the time of the repeat US-FNAB. The frequency of malignancy and the BRAF(V600E) mutation were compared between suspicious and probably benign nodules on US and between groups 1 and 2.Of 304 nodules, 113 were malignant and 59 (52.2%) had the BRAF(V600E) mutation. Also, 58 of 196 nodules suspicious on US (29.6%) had the BRAF(V600E) mutation, whereas 1 of 108 (0.9%) probably benign nodules had the BRAF(V600E) mutation (P value.0001). The BRAF(V600E) mutation was more frequently found in nodules suspicious on US than those probably benign in both groups 1 and 2 (P value.0001 and .0058, respectively). Preoperative detection of the BRAF(V600E) mutation led surgeons to perform surgery in 5.8% of 103 nodules with benign and nondiagnostic results on cytology in group 1 and 1% of 98 nodules in group 2 without treatment delay.The BRAF(V600E) mutation analysis was a useful adjunctive diagnostic tool, especially in nodules suspicious on US, and was more effective if performed at the time of the initial US-FNAB.

This study examined HIV test counselors' beliefs and practices regarding communicating indeterminate HIV test results to clients. There are many reasons for an indeterminate HIV antibody/ Western blot assay including early HIV infection, infection with other contagious diseases, autoimmune diseases, and second or subsequent pregnancies in women. Field observations of three community HIV testing sites and semistructured interviews with 16 HIV test counselors were conducted from August 2002 through June 2003. Counselors defined an indeterminate test result in different ways. They also presented several different theories of causation, yet failed to mention two potential causes of an indeterminate result, association with large animals and infection with other (non-HIV-1) HIV strains. Counselors' understanding of the meaning of an indeterminate HIV test result varied a great deal. Some counselors believed that an indeterminate result truly was ambiguous while others believed it was indicative of being either HIV-positive or HIV-negative. Counselors' primary advice to clients who received an indeterminate result was to retest immediately without a waiting period. Counselors reported that communicating indeterminate test results to clients was a challenging task because clients who received such a result were confused, angry, and/or mistrustful. Results highlight the need for further research to provide reliable estimates of the extensiveness of indeterminate HIV test results and to further assess the nature of counselor and client responses to indeterminate test results.

Background Echocardiography is important for the diagnosis of infective endocarditis (IE), for which transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE). Methods A systematic review and meta-analysis of observational studies was performed with the objective of evaluating diagnostic properties of TTE, with transesophageal findings of IE as the reference standard in patients with suspected IE. Results The literature search yielded 377 unique articles, of which 16 met the inclusion criteria. The 16 studies included 2,807 patients, of whom 793 (28%) had vegetations on TEE. For detecting vegetations, harmonic TTE had sensitivity of 61% (95% CI, 45%–75%) and specificity of 94% (95% CI, 85%–98%) with a negative likelihood ratio (NLR) of 0.42 (95% CI, 0.26–0.61). NLR for harmonic TTE can be improved by including only patients without prosthetic valves (NLR = 0.36; 95% CI, 0.22–0.55) or by having strict criteria for conclusively negative results on TTE (NLR = 0.17; 95% CI, 0.10–0.28). In the setting of patients without prosthetic valves, harmonic TTE had likelihood ratios of 0.14 (95% CI, 0.09–0.23) for a conclusively negative result, 0.66 (95% CI, 0.53–0.81) for an indeterminate result, and 14.60 (95% CI, 3.37–70.40) for a positive result. Conclusions Modern harmonic TTE still has the potential to miss many vegetations detected on TEE. When limited to patients without prosthetic valves, a conclusively negative TTE under optimal view greatly decreases likelihood of IE. All other transthoracic results are not useful for ruling out IE, and subsequent TEE is almost always required.

Background Vitamin B 12 insufficiency/deficiency is common in mixed patient populations. However there is no single marker which can reliably diagnose B 12 insufficiency/deficiency. Elevated concentrations of methylmalonic acid (MMA) are considered the most representative marker of metabolic vitamin B 12 insufficiency, but poor assay availability limits clinical utility. Low concentrations of serum vitamin B 12 are often used to assess vitamin B 12 status but this approach generates a high rate of false negative results. Emerging evidence indicates that holotranscobalamin (holoTC) may be a more reliable indicator of vitamin B 12 status. Aims and methods We substituted serum vitamin B 12 measurement with holoTC, supported by MMA in patients referred for assessment of vitamin B 12 status. A service evaluation was undertaken of the pattern of MMA values obtained for patients with holoTC 25–50 pmol/L (an indeterminate result). MMA cut-offs of 280 and 360 nmol/L were applied for patients ≤ 65 or > 65 years respectively. Results A total of 4,175 consecutive patients were investigated and MMA was analysed for 19% of patients. The incidence of elevated MMA was 41% (holoTC, 25–29 pmol/L), 32% (30–34 pmol/L), 33% (35–39 pmol/L), 30% (40–44 pmol/L), and 26% (45–50 pmol/L). Conclusions Our results indicate that in the clinical setting a holoTC between 25 and 50 pmol/L is a poor predictor for the concentration of MMA provided the goal is to identify patients with MMA values above the limits used in the present study. Further studies are needed to evaluate to what extent holoTC 50 pmol/L reflect circulatory MMA concentrations.

QuantiFERON-TB Gold In Tube (QFT-IT) assay is a highly sensitive and specific test for the diagnosis of latent tuberculosis infection. Data on the use of QFT-IT assay in children are scarce and contradictory. The aim of the study was to assess the rate of indeterminate test results and to identify the factors contributing to indeterminate results on routine use of QFT-IT assay in non-immunosuppressed children. This retrospective study included 2173 children, age range from 1 month to 18 years. Determination of interferon-gamma (IFN-γ) in peripheral blood was performed by commercial QFT-IT assay. Indeterminate test results were recorded in ten (0.46%) subjects with ages ranging from 15 months to 15 years. The value of negative control was >8.0 kIU/L in one subject, whereas in the remaining nine subjects indeterminate results were consequential to positive control (

Summary The production of slime by 130 urinary isolates of Staphylococcus saprophyticus , cultured from symptomatic females in the general community, was tested by growing them on Congo red agar. Fourteen of 130 strains (11%) were found to produce slime, 112 strains (86%) did not produce any detectable slime, while four strains (3%) gave an indeterminate result. Slime production does not appear to be an important virulence factor of S. saprophyticus causing urinary tract infection in females of childbearing age.

Commonly used immunoassays have limitations as stand-alone tests for the diagnosis of Clostridium difficile infection (CDI). In particular, the specificity of these assays means that these tests generate a relatively large number of false-positive results. We introduced a two-stage regimen for CDI as routine. Unformed stool samples received in our laboratory were initially tested with a Meridian Premier enzyme immunoassay (EIA) and positive samples were retested with reference testing methods (toxigenic culture and cell cytotoxicity assay). Clinicians received diagnostically useful information on the day that the sample arrived in the laboratory, with definitive negative and provisional positive results made available. We reviewed the first 3643 unformed stool specimens of which 158/3643 (4.3%) were provisionally positive by EIA. Of the 158 samples that were EIA positive, 119 were confirmed as being positive by at least one of the reference methods, giving a positive predictive value in this population of 75% (95% confidence interval: 67.6-81.7%). Comparison of the optical density values of the EIA lying between true and false-positive results suggests that the introduction of a second cut-off value would improve diagnostics. A test with two cut-offs would give the following results: 'positive', 'negative' and 'indeterminate result, please perform confirmatory test'. This algorithm was a simple and cost-effective method to immediately improve diagnostics, but there is an urgent need for further research in laboratory diagnosis for CDI.

SETTING: Public chest clinics, New York City. OBJECTIVE: To evaluate the association between patient characteristics and indeterminate QuantiFERON ® TB Gold (QFT-G) results and describe follow-up testing. DESIGN: Retrospective cross-sectional multivariate logistic regression analyses of patients receiving QFT-G from October 2006 to June 2008. Analyses were performed separately depending on whether the indeterminate result was due to positive (low mitogen) or negative (high nil) control failure. RESULTS: Of 28 864 individuals tested, 2058 (7%) tested positive, 26 284 (91%) negative, and 522 (2%) were indeterminate (low mitogen, n = 264; high nil, n = 258). Low mitogen results were more frequent among those aged < 10 years (OR(adj) 3.7, 95%CI 2.4-5.9), females (OR(adj) 1.4, 95%CI 1.1-1.8), Asians (OR(adj) 2.1, 95%CI 1.3-3.4) and the US-born (OR(adj) 1.9, 95%CI 1.4-2.6) and less frequent among Hispanics (OR(adj) 0.6, 95%CI 0.4-1.0). High nil results were more frequent among Hispanics (OR(adj) 1.7, 95%CI 1.0-2.8) and less frequent among the US-born (OR(adj) 0.6, 95%CI 0.5- 0.8). Among patients who received a repeat QFT-G (n = 137), 4% tested positive, 64% negative and 32% had a second indeterminate result, always of the same type. CONCLUSION: Age, race/ethnicity and sex were associated with indeterminate QFT-G results. Most follow-up tests were negative, although a modest proportion were repeatedly indeterminate. Further studies evaluating the mechanisms of QFT-G indeterminate results are needed.

Contractualists seek to publicly justify moral principles, but it seems doubtful that a set of specific principles or policies can be definitively justified. In this sense, the contractualist project has an indeterminate result: the precise content of liberal morality is open to reasonable dispute. Liberal citizens thus find themselves disagreeing about the demands of liberal morality. They require, as Locke argued, an umpire to resolve their disputes. This paper analyzes what is required of such an umpire, and then employs a four-stage argument to show that constitutional representative democracy is the uniquely justified umpiring procedure for resolving these disputes. Democratic politics, on this view, is the continuation of ethical dispute by other means.

Contemporary clinical trails that show a beneficial effect on morbidity for a novel treatment often give an indeterminate result for mortality, which may be a component of a composite primary endpoint. Although a beneficial effect on a composite endpoint is often perceived by clinicians as indicating a beneficial effect on each of the components, this is often not the case. Typically, only one or two of the morbidity components are clearly demonstrated to benefit, with an indeterminate effect on mortality and the other morbidity components. For example, consider a trial assessing the effect of a novel treatment for coronary artery disease on the composite endpoint of death or need for revascularization. A beneficial effect on this composite endpoint might be presented as a reduced risk of death and need for revascularization, but the actual benefit might be confined to a reduced need for revascularization, with an indeterminate effect on mortality. The trial then provides no information as to whether the novel treatment reduces or increases the risk of death. We cannot assume that a reduced risk of morbidity necessarily translates into a reduced risk of mortality. Further, an indeterminate result for mortality might hide an underlying modest increase in mortality that the trial is underpowered to detect. The difficulty for the clinician and indeed patients (who are increasingly demanding to be better informed on the risks and benefits of treatments) is that unless a treatment has been demonstrated to reduce mortality, the possibility of increased mortality cannot be excluded. In the light of the …

Introduction South of Tyne and Tees bowel cancer screening centres commenced screening in February 2007 as first wave centres. They serve a combined population of 1.5 million. The aims of the prospective audit were 1. To analyse the findings at colonoscopy among individuals with positive FOB in round 2 of screening and correlate this with their own results from round 1 of screening and 2. To compare findings at the first and second round of screening. Methods A prospective audit of all patients with a positive FOB screened in round one and two and undergoing colonoscopy was undertaken. For individuals undergoing the second round of screening a comparison was made with their first round of screening 2 years earlier. Individuals with an abnormal FOB result (5/6 positive windows) or a weak positive result (initial test indeterminate and subsequent strong positive or indeterminate) are invited for colonoscopy. Individuals with an initial indeterminate result then two normal FOB9s are invited for repeat FOB testing in 2 years time. Results 1490 patents were colonoscoped between 2007 and 2009 in the first round of screening and subsequently 118 patients since the second round commenced in April 2009. Of the 118 scoped as part of their second round, 109 had a negative FOB in round 1, of which six were diagnosed with cancer and nine with high-risk polyps in round 2. A further 29 had low or intermediate risk polyps, 21 abnormal not polyps and 34 were normal. Of the six patients who had weak positive then 2 normals in round 1, 3 had low or intermediate risk polyps, 1 abnormal not polyps and 2 normal. Of 3 patients with positive FOBs (colonoscoped) in round 1, 1 had low risk polyps and 2 were abnormal but not polyps in round 2. Abstract 013 compares overall findings of screening in round 1 and 2 demonstrating that cancer diagnosis was more likely in round 1. Conclusion Round 2 of screening demonstrated a high yield of pathology including six patients with cancer and nine with high-risk polyps. All of these patients had completely negative FOBs in round 1. A diagnosis of cancer was more likely in round one. Abstract submitted on behalf of the Northern Region Endoscopy Group.

In Reply .—Dr Piper and colleagues raise several issues that illustrate the difficulties of applying clinical epidemiologic methods to the field of developmental disabilities. Most tests in the clinical laboratory provide either a positive or negative result. Very few clinically useful tests give an indeterminate result. In the field of developmental disabilities, we frequently encounter children with developmental delay who do not fit more specific disease categories. In Harris' article it is unclear whether the children with developmental delay should be included in the "diseased" or "nondiseased" group. For the sake of completeness, presenting test results for these children would allow the clinician to decide in which group to include them. However, if we use Piper and colleagues' suggestion to place these children in the "nondiseased" group, this would have no effect on the sensitivity calculations shown in the article. As Piper and colleagues indicate, the predictive value of a

To the Editor. —On Jan 1, 1988, Illinois and Louisiana became the first states to begin compulsory premarital screening for human immunodeficiency virus (HIV) antibodies. The following case report of an indeterminate test result demonstrates one of several serious difficulties encountered with premarital HIV testing. Equivocal results place undue emotional stress on the engaged couple and are confounded by the time constraints of the marriage license application process. Report of a Case. —A woman in her early 20s came to the clinic for a mandatory premarital blood test. Our clinical staff had prepared extensively to provide couples with educational material and consent forms, as well as to ensure timely, accurate, and strictly confidential test results. 1 A week later the results showed a repeatedly reactive enzyme-linked immunosorbent assay result (her fiance had a negative result). Western blot assay showed an indeterminate result reactive to the p24 antigen only. She had