Evaluation of Xpert® MTB/RIF and ustar easyNAT™ TB IAD for diagnosis of tuberculous lymphadenitis of children in Tanzania : a prospective descriptive study

Fine needle aspiration biopsy has become a standard approach for diagnosis of peripheral tuberculous lymphadenitis. The aim of this study was to compare the performance of Xpert MTB/RIF and Ustar EasyNAT TB IAD nucleic acid amplification assays, against acid-fast bacilli microscopy, cytology and mycobacterial culture for the diagnosis of TB lymphadenitis in children from a TB-endemic setting in Tanzania.; Children of 8 weeks to 16 years of age, suspected of having TB lymphadenitis, were recruited at a district hospital in Tanzania. Fine needle aspirates of lymph nodes were analysed using acid-fast bacilli microscopy, liquid TB culture, cytology, Xpert MTB/RIF and EasyNAT. Latent class analysis and comparison against a composite reference standard comprising "culture and/or cytology" was done, to assess the performance of Xpert MTB/RIF and EasyNAT for the diagnosis of TB lymphadenitis.; Seventy-nine children were recruited; 4 were excluded from analysis. Against a composite reference standard of culture and/or cytology, Xpert MTB/RIF and EasyNAT had a sensitivity and specificity of 58 % and 93 %; and 19 % and 100 % respectively. Relative to latent class definitions, cytology had a sensitivity of 100 % and specificity of 94.7 %.; Combining clinical assessment, cytology and Xpert MTB/RIF may allow for a rapid and accurate diagnosis of childhood TB lymphadenitis. Larger diagnostic evaluation studies are recommended to validate these findings and on Xpert MTB/RIF to assess its use as a solitary initial test for TB lymphadenitis in children

Effect of Preanalytical Processing of ThinPrep Specimens on Detection of High-Risk Human Papillomavirus by the Aptima HPV Assay

Two important preanalytical protocols performed on liquid-based cytological specimens, namely, automated cytology processing and glacial acetic acid (GAA) treatment, may occur prior to the arrival of specimens in a molecular diagnostics laboratory. Ninety-two ThinPrep vials previously positive for high-risk human papillomavirus (HPV) via the Cervista HPV HR test were preselected and alternated with 92 previously negative ThinPrep vials. The specimen set was processed in a consecutive fashion by an automated cytology processor without fastidious decontamination precautions. Carryover potential was subsequently assessed by performance of the Aptima HPV assay on aliquots from reprocessed ThinPrep vials. All previously negative ThinPrep vials yielded a negative result following routine automated cytology processing, despite close proximity to known-positive ThinPrep vials. In separate experiments, aliquots from 236 ThinPrep vials were forwarded for tandem analysis with and without GAA treatment. Data from GAA- and mock-treated specimens generated by Aptima HPV were compared to correlate data generated by Cervista. A 99.2% concordance of Aptima HPV results from GAA-treated and mock-treated specimens was noted. This result differed from the concordance result derived from Cervista (91.5%; P \u3c 0.0002). Of the initially positive Cervista results, 21.9% reverted to negative following GAA treatment; the correlate value was 2.7% for Aptima HPV (P = 0.01). While deleterious effects of GAA treatment on genomic DNA were noted with Cervista (P = 0.0015), GAA treatment had no significant effects on Aptima HPV specimen signal/cutoff ratios or amplification of internal control RNA (P ≥ 0.07). The validity of an Aptima HPV result is independent of GAA treatment and routine automated cytology processing

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

Calibrating models in economic evaluation: a comparison of alternative measures of goodness of fit, parameter search strategies and convergence criteria.

BACKGROUND: The importance of assessing the accuracy of health economic decision models is widely recognized. Many applied decision models (implicitly) assume that the process of identifying relevant values for a model's input parameters is sufficient to prove the model's accuracy. The selection of infeasible combinations of input parameter values is most likely in the context of probabilistic sensitivity analysis (PSA), where parameter values are drawn from independently specified probability distributions for each model parameter. Model calibration involves the identification of input parameter values that produce model output parameters that best predict observed data. METHODS: An empirical comparison of three key calibration issues is presented: the applied measure of goodness of fit (GOF); the search strategy for selecting sets of input parameter values; and the convergence criteria for determining acceptable GOF. The comparisons are presented in the context of probabilistic calibration, a widely applicable approach to calibration that can be easily integrated with PSA. The appendix provides a user's guide to probabilistic calibration, with the reader invited to download the Microsoft® Excel-based model reported in this article. RESULTS: The calibrated models consistently provided higher mean estimates of the models' output parameter, illustrating the potential gain in accuracy derived from calibrating decision models. Model uncertainty was also reduced. The chi-squared GOF measure differentiated between the accuracy of different parameter sets to a far greater degree than the likelihood GOF measure. The guided search strategy produced higher mean estimates of the models' output parameter, as well as a narrower range of predicted output values, which may reflect greater precision in the identification of candidate parameter sets or more limited coverage of the parameter space. The broader convergence threshold resulted in lower mean estimates of the models' output, and slightly wider ranges, which were closer to the outputs associated with the non-calibrated approach. CONCLUSIONS: Probabilistic calibration provides a broadly applicable method that will improve the relevance of health economic decision models, and simultaneously reduce model uncertainty. The analyses reported in this paper inform the more efficient and accurate application of calibration methods for health economic decision models

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact

Objective To examine the psychosocial impact of testing positive for high risk human papillomavirus (HPV) among women attending primary cervical screening.Design Cross sectional survey.Measures were taken at baseline and one week after the receipt of HPV and cytology screening results.Setting Well women's clinic in London, UK.Population or Sample Four hundred and twenty-eight women aged 20-64 years.Methods Postal questionnaire survey.Main outcome measures Psychosocial and psychosexual outcomes were anxiety, distress and feelings about current, past and future sexual relationships.Results Women with normal cytology who tested positive for HPV (HPVdivided by) were significantly more anxious and distressed than women who were negative (HPV-) using both a state anxiety measure [F(1,267)=29, P<0.0001] and a screening specific measure of psychological distress [F(1,267)=69, P<0.0001]. Women with an abnormal or unsatisfactory smear result, who tested HPV,. were significantly more distressed than HPV- women with the same smear result [F(1,267)=8.8, P=0.002], but there was no significant difference in state anxiety. Irrespective of cytology result, HPV women reported feeling significantly worse about their sexual relationships. Approximately one-third of women who tested positive reported feeling worse about past and future sexual relationships compared with less than 2% of HPV- women.Conclusion The findings suggest that testing positive for HPV may have an adverse psychosocial impact, with increased anxiety., distress and concern about sexual relationships. Psychosocial outcomes of HPV testing need further investigation and must be considered alongside clinical and economic decisions to include HPV testing in routine cervical screening

Psychosocial impact of alternative management policies for low-grade cervical abnormalities : results from the TOMBOLA randomised controlled trial

Background: Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination. Methods: Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20–59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥8) and significant anxiety (≥11; “30-month percentages”). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance. Results: There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80–1.21) or anxiety (OR = 0.97, 95% CI 0.81–1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38–0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54–0.84). Neither anxiety nor depression differed between arms at subsequent time-points. Conclusions: There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost

Human papillomavirus genotyping among the women with cervical abnormalities in Ulaanbaatar, Mongolia

学位記番号：保博甲12

Semantic Integration of Cervical Cancer Data Repositories to Facilitate Multicenter Association Studies: The ASSIST Approach

The current work addresses the unifi cation of Electronic Health Records related to cervical cancer into a single medical knowledge source, in the context of the EU-funded ASSIST research project. The project aims to facilitate the research for cervical precancer and cancer through a system that virtually unifi es multiple patient record repositories, physically located in different medical centers/hospitals, thus, increasing fl exibility by allowing the formation of study groups “on demand” and by recycling patient records in new studies. To this end, ASSIST uses semantic technologies to translate all medical entities (such as patient examination results, history, habits, genetic profi le) and represent them in a common form, encoded in the ASSIST Cervical Cancer Ontology. The current paper presents the knowledge elicitation approach followed, towards the defi nition and representation of the disease’s medical concepts and rules that constitute the basis for the ASSIST Cervical Cancer Ontology. The proposed approach constitutes a paradigm for semantic integration of heterogeneous clinical data that may be applicable to other biomedical application domains

Portinari: A Data Exploration Tool to Personalize Cervical Cancer Screening

Socio-technical systems play an important role in public health screening programs to prevent cancer. Cervical cancer incidence has significantly decreased in countries that developed systems for organized screening engaging medical practitioners, laboratories and patients. The system automatically identifies individuals at risk of developing the disease and invites them for a screening exam or a follow-up exam conducted by medical professionals. A triage algorithm in the system aims to reduce unnecessary screening exams for individuals at low-risk while detecting and treating individuals at high-risk. Despite the general success of screening, the triage algorithm is a one-size-fits all approach that is not personalized to a patient. This can easily be observed in historical data from screening exams. Often patients rely on personal factors to determine that they are either at high risk or not at risk at all and take action at their own discretion. Can exploring patient trajectories help hypothesize personal factors leading to their decisions? We present Portinari, a data exploration tool to query and visualize future trajectories of patients who have undergone a specific sequence of screening exams. The web-based tool contains (a) a visual query interface (b) a backend graph database of events in patients' lives (c) trajectory visualization using sankey diagrams. We use Portinari to explore diverse trajectories of patients following the Norwegian triage algorithm. The trajectories demonstrated variable degrees of adherence to the triage algorithm and allowed epidemiologists to hypothesize about the possible causes.Comment: Conference paper published at ICSE 2017 Buenos Aires, at the Software Engineering in Society Track. 10 pages, 5 figure