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Abstract Objectives A multicentre study evaluating NG-Test DetecTool OXA-23 for the detection of OXA-23 carbapenemase directly from positive blood cultures (PBCs). Methods The NG-Test DetecTool OXA-23 is an immunoassay that integrates a sample preparation device. We evaluated NG-Test DetecTool OXA-23 on 189 spiked and 126 clinical PBCs. The clinical samples’ standard-of-care procedure consisted of bacterial identification from the first day of positivity by MALDI-TOF MS, conventional culture and antimicrobial susceptibility testing. The immunoassay results were verified molecularly. The strains used for the spiked samples consisted of well-characterized Acinetobacter baumannii and Proteus mirabilis strains. Results The NG-Test DetecTool OXA-23 was evaluated on 315 PBCs and revealed sensitivity of 100% (95% CI: 98.21%–100.00%) and specificity of 100% (95% CI: 96.73%–100.00%). It provided 204 true-positive results for OXA-23 in 196 bottles with carbapenem-resistant A. baumannii (CRAB) and 8 bottles with carbapenem-resistant P. mirabilis and also provided 111 true-negative results. There were no false-positive and no false-negative results. Among the 315 PBCs studied, 83 clinical blood cultures collected in the ICU of a Greek university hospital, which were tested prospectively, all yielded CRAB, and OXA-23 was correctly detected in all samples from the first day of positivity using the NG-Test DetecTool OXA-23. Conclusions The NG-Test DetecTool OXA-23 has exhibited excellent sensitivity and specificity for OXA-23 detection in PBCs and can provide valuable information for appropriate selection of antibiotic therapy and early implementation of infection control measures.

Introduction: One-step nucleic acid amplification (OSNA) for the analysis of sentinel lymph nodes is now widely used as a reliable tool for the intraoperative diagnosis of breast cancer metastasis based on the quantification of CK19 mRNA. However, discrepancies have been noted between the molecular diagnosis and histological evaluation, potentially due to differences in tissue sampling or technical limitations. Furthermore, false-negative results may occur when target mRNA expression is reduced. Case Presentation: We herein describe a 45-year-old female patient who underwent breast-conserving surgery. The final pathological stage after surgery was pT2N1aM0 (stage IIB), hormone receptor positive (HER2: 1+). An OSNA analysis of two sentinel lymph nodes revealed no metastasis, whereas touch imprint cytology of one of the lymph nodes was positive. Immunohistochemistry of the primary tumor showed a mixture of extensive CK19-negative and focal CK19-positive lesions. A genetic analysis of the CK19-negative lesion detected mutations and abnormalities, including the ESR1 amplification, FANCA deletion, STK11 deletion, TSC2 deletion, POLD1 deletion, and mutations in PIK3CA, ARID1A, NF2, SETBP1, and EP300. Of these, tumor heterogeneity and genetic alterations, including mutations in ARID1A, NF2, and EP300, in the CK19-negative lesion were hypothesized to suppress CK19 expression. Conclusion: False-negative results are more likely to occur for CK19-negative breast cancer, emphasizing the importance of incorporating complementary diagnostic methods, such as touch imprint cytology and different molecular markers. A multifaceted diagnostic approach is crucial for ensuring accurate staging and appropriate treatment planning.

Although SCNEC is based on its characteristic histology, immunohistochemistry (IHC) is commonly employed to confirm neuroendocrine differentiation (NED). The challenge here is that SCNEC may yield negative results for traditional neuroendocrine markers. To establish an IHC panel for NED, 17 neuronal, basal, and luminal markers were examined on a tissue microarray construct generated from 47 cases of 34 patients with SCNEC as a discovery cohort. A decision tree algorithm was employed to analyze the extent and intensity of immunoreactivity and to develop a diagnostic model. An external cohort of eight cases and transmission electron microscopy (TEM) were used to validate the model. Among the 17 markers, the decision tree diagnostic model selected 3 markers to classify NED with 98.4% accuracy in classification. The extent of synaptophysin (>5%) was selected as the initial parameter, the extent of CD117 (>20%) as the second, and then the intensity of GATA3 (≤1.5, negative or weak immunoreactivity) as the third for NED. The importance of each variable was 0.758, 0.213, and 0.029, respectively. The model was validated by the TEM and using the external cohort. The decision tree model using synaptophysin, CD117, and GATA3 may help confirm NED of traditional marker-negative SCNEC.

Introduction Misclassification errors have been reported in rapid diagnostic HIV tests (RDTs) in sub‐Saharan African countries. These errors can lead to missed opportunities for prevention‐of‐mother‐to‐child‐transmission (PMTCT), early infant diagnosis and adult HIV‐prevention, unnecessary lifelong antiretroviral treatment (ART) and wasted resources. Few national estimates or systematic quantifications of sources of errors have been produced. We conducted a comprehensive assessment of possible sources of misclassification errors in routine HIV testing in Zimbabwe. Methods RDT‐based HIV test results were extracted from routine PMTCT programme records at 62 sites during national antenatal HIV surveillance in 2017. Positive‐ (PPA) and negative‐percent agreement (NPA) for HIV RDT results and the false‐HIV‐positivity rate for people with previous HIV‐positive results (“known‐positives”) were calculated using results from external quality assurance testing done for HIV surveillance purposes. Data on indicators of quality management systems, RDT kit performance under local climatic conditions and user/clerical errors were collected using HIV surveillance forms, data‐loggers and a Smartphone camera application (7 sites). Proportions of cases with errors were compared for tests done in the presence/absence of potential sources of errors. Results NPA was 99.9% for both pregnant women (N = 17224) and male partners (N = 2173). PPA was 90.0% (N = 1187) and 93.4% (N = 136) for women and men respectively. 3.5% (N = 1921) of known‐positive individuals on ART were HIV negative. Humidity and temperature exceeding manufacturers’ recommendations, particularly in storerooms (88.6% and 97.3% respectively), and premature readings of RDT output (56.0%) were common. False‐HIV‐negative cases, including interpretation errors, occurred despite staff training and good algorithm compliance, and were not reduced by existing external or internal quality assurance procedures. PPA was lower when testing room humidity exceeded 60% (88.0% vs. 93.3%; p = 0.007). Conclusions False‐HIV‐negative results were still common in Zimbabwe in 2017 and could be reduced with HIV testing algorithms that use RDTs with higher sensitivity under real‐world conditions and greater practicality under busy clinic conditions, and by strengthening proficiency testing procedures in external quality assurance systems. New false‐HIV‐positive RDT results were infrequent but earlier errors in testing may have resulted in large numbers of uninfected individuals being on ART.

Background False‐negative (FN) results in cervical cancer (CC) screening pose significant risk for participants and should be audited. The aim of the study was to analyse the results of audit of FN slides collected in 2010–2013 in Polish Cervical Cancer Screening Program (CCSP) and to seek for risk factors of obtaining true‐negative result (TN; not containing abnormal cells as confirmed in audit) before CC diagnosis. Methods Screening database was merged with National Cancer Registry to identify negative slides preceding histologically confirmed CC diagnosis up to 42 months. Two blinding slides were randomly assigned per each FN. The whole set was reassessed independently by three pathologists with 30 years of experience in cytology evaluation. Final audit result was established in the case of ≥2 coherent reports. Agreement rates and kappa (κ) coefficients were calculated. Logistic analysis of risk factors for obtaining TN result was performed. Results Of 374 included FNs, 204 were considered abnormal (54.6%) and 91 were confirmed negative for intraepithelial neoplasia (24.3%). Agreement between experts was moderate for FNs (κ = 0.266) and fair for blinding slides (κ = 0.142) when grouping abnormal slides. Adenocarcinoma diagnosis elevated the risk of TN result (OR = 3.83); detection of macroscopic changes on the cervix and smoking lowered the risk (OR = 0.39, OR = 0.40 respectively). Conclusions Misinterpretation was the main reason for FN cytology in the CCSP which indicated the need of further personnel training to increase screening quality. Rather low agreement between auditors requires further insight. A standardised process of auditors' selection should be planned to increase audit quality.

Background The non‐invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false‐negative results are inevitable and important, limited false‐negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false‐negative results detected in the NIPS cases with a low‐risk result. Methods NIPS was performed using whole‐genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low‐risk result performed in our center in 2017 were followed‐up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies. Results By following‐up 10,975 low‐risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false‐negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases. Conclusion Our results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false‐negative results. In this study, we performed a comprehensive follow‐up on a cohort consisting 10975 NIPS cases with a low‐risk result from a single center, which revealed four false‐negative cases. Our study provides information regarding the etiologies of false‐negative results, which will contribute to improve both the NIPS technique and the related perinatal care in clinic.

Psychological treatments provide many benefits for patients with psychiatric disorders, but research also suggests that negative effects might occur from the interventions involved. The Negative Effects Questionnaire (NEQ) has previously been developed as a way of determining the occurrence and characteristics of such incidents, consisting of 32 items and six factors. However, the NEQ has yet to be examined using modern test theory, which could help to improve the understanding of how well the instrument works psychometrically. The current study investigated the reliability and validity of the NEQ from both a person and item perspective, establishing goodness-of-fit, item bias, and scale precision. The NEQ was distributed to 564 patients in five clinical trials at post-treatment. Data were analysed using Rasch analysis, i.e. a modern test theory application. (1) the NEQ exhibits fairness in testing across sociodemographics, (2) shows comparable validity for a final and condensed scale of 20 instead of 32 items, (3) uses a rating scale that advances monotonically in steps of 0 to 4, and (4) is suitable for monitoring negative effects on an item-level. The NEQ is proposed as a useful instrument for investigating negative effects in psychological treatments, and its newer shorter format could facilitate its use in clinical and research settings. However, further research is needed to explore the relationship between negative effects and treatment outcome, as well as to test it in more diverse patient populations.

No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.

Background COVID-19 is diagnosed via detection of SARS-CoV-2 RNA using real time reverse-transcriptase polymerase chain reaction (rtRT-PCR). Performance of many SARS-CoV-2 rtRT-PCR assays is not entirely known due to the lack of a gold standard. We sought to evaluate the false negative rate (FNR) and sensitivity of our laboratory-developed SARS-CoV-2 rtRT-PCR targeting the envelope (E) and RNA-dependent RNA-polymerase (RdRp) genes. Methods SARS-CoV-2 rtRT-PCR results at the Public Health Laboratory (Alberta, Canada) from January 21 to April 18, 2020 were reviewed to identify patients with an initial negative rtRT-PCR followed by a positive result on repeat testing within 14 days (defined as discordant results). Negative samples from these discordant specimens were re-tested using three alternate rtRT-PCR assays (targeting the E gene and N1/N2 regions of the nucleocapsid genes) to assess for false negative (FN) results. Results During the time period specified, 95,919 patients (100,001 samples) were tested for SARS-CoV-2. Of these, 49 patients were found to have discordant results including 49 positive and 52 negative swabs. Repeat testing of 52 negative swabs found five FNs (from five separate patients). Assuming 100% specificity of the diagnostic assay, the FNR and sensitivity in this group of patients with discordant testing was 9.3% (95% CI 1.5–17.0%) and 90.7% (95% CI 82.6–98.9%) respectively. Conclusions Studies to understand the FNR of routinely used assays are important to confirm adequate clinical performance. In this study, most FN results were due to low amounts of SARS-CoV-2 virus concentrations in patients with multiple specimens collected during different stages of infection. Post-test clinical evaluation of each patient is advised to ensure that rtRT-PCR results are not the only factor in excluding COVID-19.