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Viral outbreaks can cause widespread disruption, creating the need for diagnostic tools that provide high performance and sample versatility at the point of use with moderate complexity. Current gold standards such as PCR and rapid antigen tests fall short in one or more of these aspects. Here, we report a label-free and amplification-free nanopore sensor platform that overcomes these challenges via direct detection and quantification of viral RNA in clinical samples from a variety of biological fluids. The assay uses an optofluidic chip that combines optical waveguides with a fluidic channel and integrates a solid-state nanopore for sensing of individual biomolecules upon translocation through the pore. High specificity and low limit of detection are ensured by capturing RNA targets on microbeads and collecting them by optical trapping at the nanopore location where targets are released and rapidly detected. We use this device for longitudinal studies of the viral load progression for Zika and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections in marmoset and baboon animal models, respectively. The up to million-fold trapping-based target concentration enhancement enables amplification-free RNA quantification across the clinically relevant concentration range down to the assay limit of RT-qPCR as well as cases in which PCR failed. The assay operates across all relevant biofluids, including semen, urine, and whole blood for Zika and nasopharyngeal and throat swab, rectal swab, and bronchoalveolar lavage for SARS-CoV-2. The versatility, performance, simplicity, and potential for full microfluidic integration of the amplification-free nanopore assay points toward a unique approach to molecular diagnostics for nucleic acids, proteins, and other targets.

IntroductionIn high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood.MethodsWe developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs.ResultsUniversal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted.ConclusionsScreening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment of TBM, emphasizing promising future directions. RECENT FINDINGS: The molecular assay GeneXpert MTB/Rif Ultra has improved sensitivity but has inadequate negative predictive value to rule-out TBM. Evaluations of tests focused on the host response and bacterial components are ongoing. Clinical trials are in progress to explore the roles of rifampin, fluoroquinolones, linezolid, and adjunctive aspirin. Though diagnosis has improved, novel modalities are being explored to improve the rapid diagnosis of TBM. Multiple ongoing clinical trials may change current therapies for TBM in the near future.

GeneXpert MTB/RIF, a tool widely used for diagnosing tuberculosis, has limitations for detecting rifampin resistance in certain variants. We report transmission of a pre-extensively drug-resistant variant in Botswana that went undetected by GeneXpert. The public health impact of misdiagnosis emphasizes the need for comprehensive molecular testing to identify resistance and guide treatment.

INTRODUCTION: Vaccine safety surveillance commonly includes a serial testing approach with a sensitive method for signal generation and specific method for signal validation. The extent to which serial testing in real-world studies improves or hinders overall performance in terms of sensitivity and specificity remains unknown. METHODS: We assessed the overall performance of serial testing using three administrative claims and one electronic health record database. We compared type I and II errors before and after empirical calibration for historical comparator, self-controlled case series (SCCS), and the serial combination of those designs against six vaccine exposure groups with 93 negative control and 279 imputed positive control outcomes. RESULTS: The historical comparator design mostly had fewer type II errors than SCCS. SCCS had fewer type I errors than the historical comparator. Before empirical calibration, the serial combination increased specificity and decreased sensitivity. Type II errors mostly exceeded 50%. After empirical calibration, type I errors returned to nominal; sensitivity was lowest when the methods were combined. CONCLUSION: While serial combination produced fewer false-positive signals compared with the most specific method, it generated more false-negative signals compared with the most sensitive method. Using a historical comparator design followed by an SCCS analysis yielded decreased sensitivity in evaluating safety signals relative to a one-stage SCCS approach. While the current use of serial testing in vaccine surveillance may provide a practical paradigm for signal identification and triage, single epidemiological designs should be explored as valuable approaches to detecting signals.

INTRODUCTION: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI-LB) were published in 2020. The aim of this systematic review and meta-analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI-LB set out in the criteria. METHODS: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI-LB. RESULTS: Fifty-seven articles were included. The meta-analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta-iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. DISCUSSION: The available evidence largely supports the current diagnostic criteria for MCI-LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. HIGHLIGHTS: A meta-analysis of the diagnostic features of MCI-LB was carried out. The four core clinical features were more common in MCI-LB than MCI-AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI-LB. More evidence is needed for the proposed biomarkers. FDG-PET and quantitative EEG show promise as diagnostic biomarkers in MCI-LB.

BackgroundThe World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L-1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs).MethodsFollowing a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal-external cross-validation to evaluate performance.ResultsWe pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L-1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L-1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively.ConclusionsCRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L-1 cut-off or in a CPM depends on available resources.

ObjectiveWe performed a scoping review of algorithms using electronic health record (EHR) data to identify patients with Alzheimer's disease and related dementias (ADRD), to advance their use in research and clinical care.Materials and methodsStarting with a previous scoping review of EHR phenotypes, we performed a cumulative update (April 2020 through March 1, 2023) using Pubmed, PheKB, and expert review with exclusive focus on ADRD identification. We included algorithms using EHR data alone or in combination with non-EHR data and characterized whether they identified patients at high risk of or with a current diagnosis of ADRD.ResultsFor our cumulative focused update, we reviewed 271 titles meeting our search criteria, 49 abstracts, and 26 full text papers. We identified 8 articles from the original systematic review, 8 from our new search, and 4 recommended by an expert. We identified 20 papers describing 19 unique EHR phenotypes for ADRD: 7 algorithms identifying patients with diagnosed dementia and 12 algorithms identifying patients at high risk of dementia that prioritize sensitivity over specificity. Reference standards range from only using other EHR data to in-person cognitive screening.ConclusionA variety of EHR-based phenotypes are available for use in identifying populations with or at high-risk of developing ADRD. This review provides comparative detail to aid in choosing the best algorithm for research, clinical care, and population health projects based on the use case and available data. Future research may further improve the design and use of algorithms by considering EHR data provenance.

Reducing the age of first autism diagnosis facilitates access to critical early intervention services. A current "waitlist crisis" for autism diagnostic evaluation thus demands that we consider novel use of available clinical resources. Previous work has found that expert autism clinicians can identify autism in young children with high specificity after only a brief observation; rapid identification by non-experts remains untested. In the current study, 252 children ages 12-53 months presented for a comprehensive autism diagnostic evaluation. We found that junior clinicians in training to become autism specialists (n = 29) accurately determined whether or not a young child would be diagnosed with autism in the first five minutes of the clinic visit in 75% of cases. Specificity of brief observations was high (0.92), suggesting that brief observations may be an effective tool for triaging young children toward autism-specific interventions. In contrast, the lower negative predictive value (0.71) of brief observations, suggest that they should not be used to rule out autism. When trainees expressed more confidence in their initial impression, their impression was more likely to match the final diagnosis. These findings add to a body of literature showing that clinical observations of suspected autism should be taken seriously, but lack of clinician concern should not be used to rule out autism or overrule other indicators of likely autism, such as parent concern or a positive screening result.

Abstract To compare the urine Congo‐red dot paper test (CRD) with dipstick urinalysis to screen preeclampsia (PE). A total of 409 paired spot urine samples were obtained prospectively from women with suspected pre‐eclampsia attending for routine hospital visits. Congo‐red dot paper test and dipstick urinalysis were examined and compared to screen pre‐eclampsia. The agreement between the two urinary test is modest (kappa coefficient = 0.28, 95% CI 0.14–0.42). The specificity of CRD was higher than urinalysis (97.4% vs. 90.4%, p

Kasper Bonnesen,1,2 Morten Schmidt1– 3 1Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Cardiology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Kasper Bonnesen, Aarhus University, Olof Palmes Allé 43– 45, 8200 Aarhus N, Denmark, Tel +45 87 16 72 12, Email bonnesen@clin.au.dkPurpose: Hypertension is an important risk factor in cardio-epidemiological research, but data quality remains a concern. We validated different registry-based definitions of hypertension.Patients and Methods: The cohort included all first-time responders of the Danish National Health Surveys (2010, 2013, or 2017). Prescription-defined hypertension was defined as ≥ 1 or ≥ 2 filled prescriptions of antihypertensive specific drugs in ≥ 1 or ≥ 2 different antihypertensive drug classes within 90, 180, or 365 days before survey response. Hospital-diagnosed hypertension was defined from hypertension diagnoses within five years before the survey response. Considering self-reported hypertension as the reference, we calculated the positive predictive value (PPV), the negative predictive value (NVP), the sensitivity, and the specificity of prescription-defined and hospital-diagnosed hypertension.Results: Among 442,490 survey responders, 127,247 (29%) had self-reported hypertension. For prescription-defined hypertension with 365-day lookback, the PPV was highest for ≥ 2 prescriptions in ≥ 2 drug classes (94%) and lowest for ≥ 1 prescription in ≥ 1 drug class (85%). The NPV was highest for ≥ 1 prescription in ≥ 2 drug classes (94%) and lowest for ≥ 1 prescription in ≥ 2 drug classes (80%). The sensitivity was highest for ≥ 1 prescription in ≥ 1 drug class (79%) and lowest for ≥ 2 prescriptions in ≥ 2 drug classes (30%). The specificity was ≥ 94% for all algorithms. The PPV and specificity did not change noteworthy with length of lookback period, whereas the NPV and the sensitivity generally were higher for longer lookback. The algorithm ≥ 1 prescription in ≥ 2 drug classes with 365-day lookback was among the best balanced across all measures of validity (PPV=88%, NPV=94%, sensitivity=75%, specificity=96%). For hospital-diagnosed hypertension, the PPV was 90%, the NPV was 76%, the sensitivity was 22%, and the specificity was 99%.Conclusion: Compared with self-reported hypertension, the algorithms for prescription-defined and hospital-diagnosed hypertension had high predictive values and specificity, but low sensitivity.Keywords: epidemiologic studies, epidemiology, hypertension, predictive value of tests, sensitivity and specificity, validation study

Abstract Background Accurate assessment of breast implants is important for appropriate clinical management. We evaluated silicone properties and diagnostic accuracy for characterizing silicone implants and detecting degenerative changes including rupture in photon-counting computed tomography (PCCT). Methods Over 16 months, we prospectively included patients with silicone implants and available breast magnetic resonance imaging (MRI) who received thoracic PCCT performed in prone position. Consensus reading of all available imaging studies including MRI served as reference standard. Two readers evaluated all implants in PCCT reconstructions for degenerative changes. In a subgroup of implants, mean density of silicone, adjacent muscle, and fat were measured on PCCT reconstructions. Contrast-to-noise ratios (CNRs) were calculated for implant-to-muscle and implant-to-fat. Results Among 21 subjects, aged 60 ± 13.1 years (mean ± standard deviation) with 29 implants PCCT showed the following: high accuracy for linguine sign, intraimplant fluid (all > 0.99), peri-implant silicone (0.95), keyhole sign (0.90), and folds of the membrane (0.81); high specificity for linguine sign, intraimplant fluid, keyhole sign, folds of the membrane (all > 0.99), and peri-implant silicone (0.98); and high sensitivity for linguine sign and intraimplant fluid (all > 0.99). In a subgroup of 12 implants, the highest CNR for implant-to-muscle was observed on virtual unenhanced reconstructions (20.9) and iodine maps (22.9), for implant-to-fat on iodine maps (27.7) and monoenergetic reconstructions (31.8). Conclusions Our findings demonstrate that silicone breast implants exhibit distinct contrast properties at PCCT, which may provide incremental information for detection of degenerative changes and rupture of implants. Relevance statement Thoracic photon-counting computed tomography is a promising modality for the diagnostic assessment of silicone breast implants. Key points • Thoracic photon-counting computed tomography demonstrates unique contrast properties of silicone breast implants. • Iodine map reconstructions reveal strong contrast-to-noise ratios for implant-to-muscle and implant-to-fat. • Thoracic photon-counting computed tomography shows high diagnostic accuracy in detecting implant degeneration and rupture. Trial registration German Clinical Trials Register number DRKS00028997, date of registration 2022–08-08, retrospectively registered. Graphical Abstract

Background Autism spectrum disorder (ASD) requires trained professionals for its adequate diagnosis. There is a shortage of such professionals in Brazil. Screening tools could identify priority cases. The only instrument for that in Brazilian Portuguese is employed for toddlers up to 2.5 years old.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two‐stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log‐rank statistics for true biomarker status strata. These adjusted log‐rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component‐wise hypothesis. We discuss the power analysis with the control of the type‐I error rate by using the correlations between the adjusted log‐rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall‐cell lung cancer. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectivesMaterial and MethodsResultsConclusions and SignificanceNon-Echo-Planar Diffusion Weighed Magnetic Resonance Imaging (non-EPI DW MRI) plays a role in the planning of cholesteatoma surgery.To outline the usage of Non-EPI DW MRI in cholesteatoma diagnostics and to determine its accuracy, using otosurgery diagnostics as reference standard.A retrospective descriptive study. All subjects operated, with suspicion of cholesteatoma as indication, that had a preceding examination with non-EPI DW MRI, between October 2010 and March 2019. Calculating sensitivity, specificity, predicative values, and likelihood ratios, using non-EPI DW MRI as index test and diagnosis from otosurgery as reference standard.Fifty-two subject episodes were included. Non-EPI DW MRI had a sensitivity of 0.50, specificity of 0.75, positive and negative predictive values of 0.74 and 0.52 and, positive and negative likelihood ratios of 2.0 and 0.67 respectively.There is a clear annual trend with increased numbers of executed examinations during the study period. The diagnostic accuracy of non-EPI DW MRI does not reach acceptable levels in the existing everyday routine practice conditions. The accuracy of the examination increases when interpreted by an experienced radiologist and when using the definition of cholesteatoma recommended by EAONO/JOS. [ABSTRACT FROM AUTHOR]

The most common cause of bacterial pharyngitis is Group A Streptococcus (GAS). Accurate diagnosis of GAS pharyngitis is crucial to identify children who would benefit from antibiotic treatment. Rapid diagnosis has the potential to reduce antibiotic overuse. Current national guidelines differ in their recommendations for GAS testing. While rapid antigen detection tests (RADTs) are widely used, their sensitivity is considered too low for stand-alone testing by several expert bodies. Newer molecular tests using nucleic acid amplification show higher accuracy and fast results, but their cost, complexity, and very high sensitivity may limit widespread adoption. This review provides up-to-date evidence regarding rapid diagnostic testing and antimicrobial stewardship in children with sore throat. We discuss discrepancies across GAS testing guidelines at the international level, patient selection for testing for GAS, rapid test accuracy, and the potential role of rapid GAS tests to promote antibiotic stewardship, with emphasis on emerging rapid molecular tests. [ABSTRACT FROM AUTHOR]

To compare the urine Congo‐red dot paper test (CRD) with dipstick urinalysis to screen preeclampsia (PE). A total of 409 paired spot urine samples were obtained prospectively from women with suspected pre‐eclampsia attending for routine hospital visits. Congo‐red dot paper test and dipstick urinalysis were examined and compared to screen pre‐eclampsia. The agreement between the two urinary test is modest (kappa coefficient = 0.28, 95% CI 0.14–0.42). The specificity of CRD was higher than urinalysis (97.4% vs. 90.4%, p <.001). Urinalysis performed better in sensitivity (77.3% vs. 40.9%, p =.04) and the area under the receiver operating characteristic curves (AUC) (0.84 [95% CI 0.74–0.94] vs. 0.69 [95% CI 0.55–0.83], p =.04) than CRD, respectively. The sensitivity, specificity, AUC of the parallel test of them is 86.4% (64.0%–96.4%), 89.1% (85.5%–92.0%), and 0.88 (95% CI 0.79–0.96). And the serial test is 31.8% (14.7%–54.9%), 98.7% (96.8%–99.5%), 0.65 (95% CI 0.51–0.79), accordingly. The urinalysis is a better diagnosing test for preeclampsia. CRD could aid in the diagnosis of patients with preeclampsia. Combined the two tests in suspected patients may further improve the performance in the diagnosis of preeclampsia. Further study need to be made for its potential clinical practice. [ABSTRACT FROM AUTHOR]

Background Appropriate conceptualization and measurement of disability are critical for population-focused resource allocation and policy development. Self-reported and performance-based measures of functioning have been used to represent disability. Variation in environmental context or self-perception of ability may influence self-reports; however, performance-based measures that attempt to control environmental context may not accurately capture real-world aspects of functioning. This study examined the agreement between self-report and performance-based measures of functioning within 4 domains among older adults. Methods Cross-sectional data from the 2021 National Health and Aging Trends Study was used. Self-reported and performance-based measures of functioning were assessed for vision, hearing, mobility, and memory domains. We examined the diagnostic characteristics of performance-based versus self-reported measures using sensitivity, specificity, and receiver operating characteristics curves. Differences in the agreement of these measures across sociodemographic groups were investigated using logistic regression. Results Among 2 442 respondents 71 years and older (mean 78.5 ± 5.3, 56% female participants), performance measures of hearing and mobility had high sensitivity (89% and 91%, respectively) and low/moderate specificity (36% and 63%, respectively). The sensitivity and specificity of vision measures were 71%. Memory measures had high specificity (89%) and low sensitivity (28%). Performance-based discrimination ranged from 0.59 (memory) to 0.78 (mobility). Agreement varied across sociodemographic factors. Conclusions Performance measures diverge from self-reported functioning among older adults. Discordance may reveal opportunities for environmental intervention where participants' performance does not capture the full extent of barriers in their daily lives. Additional research is needed to investigate individual and environmental factors which could explain the observed differences. [ABSTRACT FROM AUTHOR]

Purpose: To determine the diagnostic value of seven injury history variables, nine clinical tests (including the combination thereof) and overall clinical suspicion for complete discontinuity of the lateral ankle ligaments in the acute (0–2 days post‐injury) and delayed setting (5–8 days post‐injury). Methods: All acute ankle injuries in adult athletes (≥18 years) presenting up to 2 days post‐injury were assessed for eligibility. Athletes were excluded if imaging studies demonstrated a frank fracture or 3 T MRI could not be acquired within 10 days post‐injury. Using standardized history variables and clinical tests, acute clinical evaluation was performed within 2 days post‐injury. Delayed clinical evaluation was performed 5–8 days post‐injury. Overall, clinical suspicion was recorded after clinical evaluation. MRI was used as the reference standard. Results: Between February 2018 and February 2020, a total of 117 acute ankle injuries were screened for eligibility, of which 43 were included in this study. Complete discontinuity of lateral ankle ligaments was observed in 23 (53%) acute ankle injuries. In the acute setting, lateral swelling had 100% (95% confidence interval [CI]: 82–100) sensitivity, haematoma had 85% (95% CI: 61–96) specificity and the anterior drawer test had 100% (95% CI: 77–100) specificity. In the delayed setting, sensitivity for the presence of haematoma improved from 43% (95% CI: 24–65) to 91% (95% CI: 70–98; p < 0.01) and the sensitivity of the anterior drawer test improved from 21% (95% CI: 7–46) to 61% (95% CI: 39–80; p = 0.02). Clinical suspicion had a positive likelihood ratio (LR) of 4.35 (95% CI: 0.55–34.17) in the acute setting and a positive LR of 6.09 (95% CI: 1.57–23.60) in the delayed setting. Conclusions: In the acute setting, clinical evaluation can exclude complete discontinuity (e.g., absent lateral swelling) and identify athletes with a high probability of complete discontinuity (e.g., positive anterior drawer test) of the lateral ankle ligaments. In the delayed setting, the sensitivity of common clinical findings increases resulting in an improved diagnostic accuracy. In clinical practice, this study underlines the importance of meticulous clinical evaluation in the acute setting. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis. We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012–2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472). Seven independent studies (N = 305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n = 3; 148 subjects) and low quality (n = 4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89–98; I 2 = 23%) and 88% (95% CI, 83–92; I 2 = 83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3–222.2; I 2 = 30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92–0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity. Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis. [ABSTRACT FROM AUTHOR]

Objectives: The Alberta Stroke Program Early CT Score (ASPECTS) is a semi-quantitative method to evaluate the severity of early ischemic change on non-contrast computed tomography (NCCT) in patients with acute ischemic stroke (AIS). In this work, we propose an automated ASPECTS method based on large cohort of data and machine learning. Methods: For this study, we collected 3626 NCCT cases from multiple centers and annotated directly on this dataset by neurologists. Based on image analysis and machine learning methods, we constructed a two-stage machine learning model. The validity and reliability of this automated ASPECTS method were tested on an independent external validation set of 300 cases. Statistical analyses on the total ASPECTS, dichotomized ASPECTS, and region-level ASPECTS were presented. Results: On an independent external validation set of 300 cases, for the total ASPECTS results, the intraclass correlation coefficient between automated ASPECTS and expert-rated was 0.842. The agreement between ASPECTS threshold of ≥ 6 versus < 6 using a dichotomized method was moderate (κ = 0.438, 0.391–0.477), and the detection rate (sensitivity) was 86.5% for patients with ASPECTS threshold of ≥ 6. Compared with the results of previous studies, our method achieved a slight lead in sensitivity (67.8%) and AUC (0.845), with comparable accuracy (78.9%) and specificity (81.2%). Conclusion: The proposed automated ASPECTS method driven by a large cohort of NCCT images performed equally well compared with expert-rated ASPECTS. This work further demonstrates the validity and reliability of automated ASPECTS evaluation method. Clinical relevance statement: The automated ASPECTS method proposed by this study may help AIS patients to receive rapid intervention, but should not be used as a stand-alone diagnostic basis. Key Points: NCCT-based manual ASPECTS scores were poorly consistent. Machine learning can automate the ASPECTS scoring process. Machine learning model design based on large cohort data can effectively improve the consistency of ASPECTS scores. [ABSTRACT FROM AUTHOR]

PurposeComparison of the performance of high-resolution susceptibility weighted imaging with standard MR sequences and MR venography to identify cortical vein clots.MethodsA retrospective review of 51 consecutive cases of cerebral venous thrombosis and 27 controls was performed with independent analysis of all MR sequences. Reference standard was obtained with consensus in a separate session by reviewing all MR sequences together.ResultsCortical vein clots were observed in 30 cases including 9 males and 21 females in the age range of 1 month to 70 years (Mean 34.9 ± 20.2 years). Sensitivity, specificity, negative predictive value, positive predictive value and accuracy of susceptibility weighted imaging for the identification of cortical vein clots were 0.93, 1.0, 1.0, 0.96 and 0.97 respectively. For all other sequences, sensitivity ranged from 0.06 to 0.39 and accuracy from 0.60 to 0.73. Combination of all sequences yielded a value of 1.0 for sensitivity, specificity, positive predictive value, negative predictive value and accuracy for the detection of cortical vein clots. Significant result for area under the receiver operating curve was observed only for SWI with a value of 0.91 (p - .000).ConclusionSusceptibility weighted imaging demonstrates the best sensitivity and accuracy among standard MR sequences including MR venography for the detection of early stage cortical vein clots. However, it needs to be interpreted in combination with other MR sequences for the most accurate evaluation of cortical vein clots.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, exposed a pressing need for new public health tools for pathogen detection, disease diagnosis, and viral genotyping. REVEALR (RNA-encoded viral nucleic acid analyte reporter) is an isothermal DNAzyme-based point-of-care diagnostic that functions with a detection limit of ∼10 copies/μL when coupled with a preamplification step and can be utilized for viral genotyping of SARS-CoV-2 variants of concern through base pair mismatch recognition in a competitive binding format. Here, we describe an advanced REVEALR platform, termed digital droplet REVEALR (ddREVEALR), that can achieve direct viral detection and absolute sample quantitation utilizing a signal amplification strategy that relies on chemical modifications, DNAzyme multiplexing, and volume compression. Using an AI-assisted image-based readout, ddREVEALR was found to achieve 95% positive predictive agreement from a set of 20 nasal pharyngeal swabs collected at UCI Medical Center in Orange, California. We propose that the combination of amplification-free and protein-free analysis makes ddREVEALR a promising application for direct viral RNA detection of clinical samples.

Since its initial release in 2011, the Liver Imaging Reporting and Data System (LI-RADS) has evolved and expanded in scope. It started as a single algorithm for hepatocellular carcinoma (HCC) diagnosis with CT or MRI with extracellular contrast agents and has grown into a multialgorithm network covering all major liver imaging modalities and contexts of use. Furthermore, it has developed its own lexicon, report templates, and supplementary materials. This article highlights the major achievements of LI-RADS in the past 11 years, including adoption in clinical care and research across the globe, and complete unification of HCC diagnostic systems in the United States. Additionally, the authors discuss current gaps in knowledge, which include challenges in surveillance, diagnostic population definition, perceived complexity, limited sensitivity of LR-5 (definite HCC) category, management implications of indeterminate observations, challenges in reporting, and treatment response assessment following radiation-based therapies and systemic treatments. Finally, the authors discuss future directions, which will focus on mitigating the current challenges and incorporating advanced technologies. Tha authors envision that LI-RADS will ultimately transform into a probability-based system for diagnosis and prognostication of liver cancers that will integrate patient characteristics and quantitative imaging features, while accounting for imaging modality and contrast agent.

Gastroesophageal reflux disease (GERD) is primarily diagnosed based on symptoms and response to a proton-pump inhibitor (PPI) trial. Gold standard testing requires an invasive endoscopic procedure, often with ambulatory pH monitoring. Salivary pepsin is a potential noninvasive modality for GERD diagnosis. This study aimed to assess diagnostic performance of salivary pepsin thresholds for GERD and determine optimal collection protocol of saliva in an external validation cohort. Over 10 months, adults with symptoms of GERD undergoing esophagogastroduodenoscopy with wireless pH-monitoring off PPI were enrolled. Saliva was self-collected by participants over 4 days across three different time points: fasting ante meridiem (AM), post-prandial, and bedtime (PM). Pepsin levels were calculated via Peptest. Pepsin variability and agreement were determined using linear mixed effects models and intraclass correlation. Validation of diagnostic threshold and performance characteristics were evaluated by receiver-operator curve analysis. Twenty participants enrolled in the study; 50% with physiologic acid exposure (acid exposure time

The Wellness Ready Test (WRT) is a lateral flow, stall-side assay that measures equine insulin in whole blood and requires validation before recommending clinical use. We evaluated intra- and inter-assay precision and linearity and compared the WRT with a radioimmunoassay (RIA). Tested concentrations ranged from 695 pmol/L (100 μIU/mL). For 20 replicates at each insulin level, intra-assay CVs of the WRT for insulin were 13.3%, 12.9%, and 15.3% at low (139-278 pmol/L; 20-40 μIU/mL), intermediate (278-417 pmol/L; 40-60 μIU/mL), and high (>417 pmol/L; >60 μIU/mL) concentrations, respectively. For 10 replicates at each level (3 assay lots), inter-assay CVs were 15.9%, 11.0%, and 11.7%, respectively. In the weighted linear regression of 5 measured insulin concentrations against expected concentrations, R2 = 0.98, slope = 1.02, and y-intercept = 14.4 pmol/L (2.08 μIU/mL). The Spearman correlation coefficient (rs) was 0.90 (95% CI: 0.85-0.94) between the WRT and RIA; the WRT = f(RIA) Passing-Bablok regression yielded the fit, y = 1.005x + 24.3 pmol/L (3.50 μIU/mL). The WRT result averaged 10.4% higher than the RIA result, with targeted bias of 25.9, 26.1, and 26.7 pmol/L (3.74, 3.76, and 3.84 μIU/mL) for cutoffs used to diagnose insulin dysregulation of 312, 347, and 451 pmol/L (45, 50, and 65 μIU/mL). Assay clinical sensitivities, specificities, and accuracies determined at the 3 selected clinical cutoffs and using the RIA as gold standard were 87-95%, 92-96%, and 91-95%, respectively (n = 99 samples). Observed total error was 28.4-30.4%. The WRT had acceptable precision, excellent linearity, and good association with the RIA.

Abstract Objectives Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. Methods Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. Results Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. Conclusions [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. Critical relevance statement Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. Key points • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach. Graphical Abstract

Kamille Herskind,1 Peter Bjødstrup Jensen,1 Christina Anne Vinter,2– 4 Lone Krebs,5,6 Lene Friis Eskildsen,5 Anne Broe,1,7 Anton Pottegård,1 Mette Bliddal1,8 1Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Gynaecology and Obstetrics, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; 5Department of Obstetrics and Gynecology, Copenhagen University Hospital-Amager and Hvidovre, Copenhagen, Denmark; 6Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 7IQVIA, London, UK; 8Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Mette Bliddal, OPEN, Heden 16, St.tv, Odense, 5000, Denmark, Tel +45 2943 7912, Email mette.bliddal@rsyd.dkPurpose: This study aimed to systematically evaluate the validity of variables related to pregnancy, delivery, and key characteristics of the infant in the Danish National Patient Register using maternal medical records as the reference standard.Patients and Methods: We reviewed medical records of 1264 women giving birth in the Region of Southern Denmark during 2017. We calculated positive (PPV) and negative (NPV) predictive values, sensitivity, and specificity to estimate the validity of 49 selected variables.Results: The PPV was ≥ 0.90 on most pregnancy-related variables including parity, pre-gestational BMI, diabetes disorders, and previous cesarean section, while it was lower for hypertensive disorders, especially mild to moderate preeclampsia (0.49, 95% CI 0.32– 0.66). Sensitivity ranged from 0.80 to 1.00 on all pregnancy-related variables, except hypertensive disorders (sensitivity 0.38– 0.71, lowest for severe preeclampsia). On most delivery-related variables including obstetric surgical procedures (eg cesarean section and induction of labor), pharmacological pain-relief, and gestational age at delivery, PPV’s ranged from 0.98 to 1.00 and the corresponding sensitivities from 0.87 to 1.00. Regarding infant-related variables, both the APGAR score registered five minutes after delivery and birthweight yielded a PPV of 1.00.Conclusion: Obstetric coding in the Danish National Patient Register shows very high validity and completeness making it a valuable source for epidemiologic research.Plain Language Summary: Danish register data are often used for epidemiological research in reproduction. The registers are based on coded information to the registers based on information from medical records. The quality of the register data is highly dependent of the validity of the codes. Yet there is a lack in our knowledge of the validity of data related to pregnancy, childbirth, and the characteristics of the newborn baby. We therefore aimed to validate the Danish National Patient Registry data related to pregnancy and childbirth by comparing the registered code with information from the medical records.We scrutinized medical records from 1264 women giving birth in the Region of Southern Denmark during 2017. We compared the registration in the medical record with the registered code in the Danish National Patient Registry by calculating how accurate the register data are according to 49 different variables.Results showed that registered codes in the Patient Registry for pregnancy- and childbirth-related conditions and key infant characteristics were to a high degree in agreement with the data from the medical report with few exceptions.In conclusion, the study revealed that the Danish National Patient Register provides highly accurate and comprehensive data for most pregnancy, delivery, and infant-related variables. This underscores the register’s value as a reliable source for epidemiologic research in reproductive health.Keywords: registries, sensitivity and specificity, validity, epidemiology, pregnancy, delivery

Background/Aim. Chronic obstructive pulmonary disease (COPD) is a chronic process that progresses with exacerbations. Various studies are carried out to predict mortality. Among the routine tests used to monitor and treat disease in the emergency department, special efforts are made to find those that are meaningful and diagnostic. The aim of the study was to compare the DECAF score and DECAF+Lactate score and examine the significance of the DECAF+Lactate score in predicting mortality in critically ill patients presenting with COPD exacerbation. Methods. This prospective multicentric study included 435 patients recruited from two centers. Patients who presented to the emergency department with acute COPD exacerbation and fit the definition of critically ill according to the quick Sequential Organ Failure Assessment (qSOFA) were included in the study. The prognostic values of the scores were compared using the receiver operating characteristic (ROC) curve analysis. The efficiency of scoring 28-day mortality was compared with logistic regression analysis. Results. For 435 patients, sensitivity, specificity, and area under the curve (AUC) were calculated for lactate, DECAF score, and DECAF+Lactate score, which were statistically significant in the ROC curve analysis for predicting mortality: 50%, 90.2%, 0.711, odds ratio (OR): 0.622 [95% confidence interval (CI): 1.573–2.203]; 57.6%, 64.3%, 0.654, OR: 0.618 (95%CI: 1.501–2.291); 60.1%, 75.4%, 0.744, OR: 0.790 (95%CI: 1.826–2.659), respectively. Each unit increase in the DECAF+Lactate score increased the risk of mortality by 2.203. Conclusion. As a result of our study, we believe that the DE-CAF+Lactate score is a more effective scoring system than the DECAF score as a predictor of mortality in critically ill patients with COPD exacerbation.

Abstract Background The sensitivity of HIV screening assays often leads to a high rate of false-positive results, requiring retests and confirmatory tests. This study aimed to analyze the capability of signal-to-cutoff (S/CO) ratios of HIV screening assay to predict HIV infection. Methods A retrospective study on the HIV screening-positive population was performed at Zhongshan Hospital, Xiamen University, the correlation between HIV screening assay S/CO ratios and HIV infection was assessed, and plotted Receiver Operating Characteristic (ROC) curves were generated to establish the optimal cutoff value for predicting HIV infection. Results Out of 396,679 patients, 836 were confirmed to be HIV-infected, with an HIV prevalence of 0.21%. The median S/CO ratios in HIV infection were significantly higher than that in non-HIV infection (296.9 vs. 2.41, P

Background and aim: Considering the importance of early detection of breast cancer and the use of non-invasive methods, the present study was conducted to evaluate the role of exosome-derived miRNA in breast cancer diagnosis. Material and methods: In the present systematic review and meta-analysis, information about exosome-derived miRNA in breast cancer diagnosis in all articles published up until the end of July 2023 was collected by two trained researchers individually using keywords and combinations of keywords from databases PubMed, Scopus, Science Direct, ISI, Web of Knowledge, Elsevier, Wiley, and Embase and Google Scholar. STATA (version 17) was used to analyze data using the fixed effects model in meta-analysis; p values less than 0.05 were considered significant. Results: A total of six studies were included in the meta-analysis process. The sensitivity and specificity of plasma-based exosomal miRNAs were 68% (ES, 95% CI: 0.39, 0.97) and 82% (ES, 95% CI: 0.52, 1.11), respectively. The sensitivity and specificity of serum-based exosomal miRNAs were 67% (ES, 95% CI: 0.33, 1.01) and 88% (ES, 95% CI: 0.54, 1.22), respectively. Conclusions: Exosomal miRNAs have high sensitivity and specificity in breast cancer diagnosis and can be considered a valuable and promising tool for early detection of breast cancer non-invasively.

BACKGROUND: Rapid IgM/IgG antibody tests were largely used in lieu of RT-PCR tests as part of COVID-19 public health response activities in Lima, Peru. To assess their utility, we explored the relationship between the time since onset of several COVID-19-related symptoms and the sensitivity of a rapid combined IgM/IgG antibody test. METHODS: We collected data from a community sample of individuals (n = 492) who received concurrent RT-PCR and rapid IgM/IgG antibody testing between May 2020 and March 2021. We estimated the sensitivity of the antibody test, against the RT-PCR test, by weeks since symptom onset via segmented regression analysis. RESULTS: The overall sensitivity of the rapid IgM/IgG antibody test was 46.7% (95% CI, 42.4-51.2%). Among 372 (75.6%) participants who reported COVID-19-related symptoms, sensitivity increased from 30.4% (95% CI, 24.7-36.6%) in week 1 after symptom onset to 83.3% (95% CI, 41.6-98.4%) in week 4. The test sensitivity increased by 31.9% (95% CI, 24.8-39.0%) per week until week 2 to 3, then decreased by - 6.0% (95% CI, - 25.7-13.7%) per week thereafter. CONCLUSION: Rapid antibody tests are a poor substitute for RT-PCR testing, regardless of presenting symptoms. This highlights the need for future pandemic planning to include timely and equitable access to gold-standard diagnostics, treatment, and vaccination.

OBJECTIVE: Most health care personnel (HCP) reporting symptoms consistent with COVID-19 illness are assessed by high-accuracy SARS-CoV-2 assays performed in clinical laboratories, but the results of such assays typically are not available until the following day. METHODS: This is an observational study over 16 weeks of a rapid nucleic acid amplification test (NAAT) performed at point of contact. The benchmark for comparison was a simultaneously obtained specimen assayed by a routine NAAT assay performed in a clinical laboratory. RESULTS: There were 577 paired rapid and routine NAAT results. Rapid test positive predictive value was 90.0% (95% confidence interval = 88.8%-91.2%), and negative predictive value was 95.2% (95% confidence interval = 93.5%-96.9%). The rapid test avoided an estimated 160 to 184 lost work shifts over 4 months. CONCLUSIONS: A rapid NAAT test-based strategy proved effective in safely clearing symptomatic employees without infection for earlier return to work.

BACKGROUND: Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period. METHODS: Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the Fungitell® BDG assay for the outcome of proven or probable IFD. RESULTS: A total of 51 patients (out of 290 patients in the parent trial) contributed blood specimens. In total, 278 specimens were evaluated. Specificity was 80.8% (95% confidence interval [CI]: 75.6%-85.3%), and NPV was over 99% (95% CI: 86.8%-99.9%). However, there were no true positive results, resulting in sensitivity of 0% (95% CI: 0.0%-84.2%) and PPV of 0% (95% CI: 0.0%-6.7%). CONCLUSIONS: Fungitell® BDG screening is of limited utility in diagnosing IFD in the post-HCT period, mainly due to high false-positive rates. Fungitell® BDG surveillance testing should not be performed in children during the early post-HCT period while receiving antifungal prophylaxis as the pretest probability for IFD is low.

BackgroundDecentralised molecular testing for tuberculosis could reduce missed diagnoses and losses to follow-up in high-burden settings. The aim of this study was to evaluate the cost and cost-effectiveness of the Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) study strategy, a multicomponent strategy including decentralised molecular testing for tuberculosis, in Uganda.MethodsWe conducted a costing and cost-effectiveness analysis nested in a pragmatic cluster-randomised trial of onsite (decentralised) versus hub-and-spoke (centralised) testing for tuberculosis with Xpert MTB/RIF Ultra (Xpert) in 20 community health centres in Uganda. We collected empirical data on the cost of the XPEL-TB strategy (decentralised Xpert testing, workflow redesign, and performance feedback) and routine tuberculosis testing (onsite smear microscopy with specimen transport for centralised Xpert testing) from the health system perspective. Time-and-motion studies were performed to estimate activity-based service costs. Cost-effectiveness was assessed as the incremental cost (2019 US$) per tuberculosis diagnosis and per 14-day treatment initiation.FindingsThe XPEL-TB study ran from Oct 22, 2018, to March 1, 2020. Effectiveness and cost-effectiveness outcomes were assessed from Dec 1, 2018, to Nov 30, 2019 and included 4867 women and 3139 men. On a per-test basis, the cost of decentralised ($20·46, range $17·85-25·72) and centralised ($18·20, range $16·58-24·25) Xpert testing was similar. However, decentralised testing resulted in more patients receiving appropriate Xpert testing, so the per-patient cost of decentralised testing was higher: $20·28 (range $17·68-25·48) versus $9·59 (range $7·62-14·34). The XPEL-TB strategy was estimated to cost $1332 (95% uncertainty range $763-5558) per incremental tuberculosis diagnosis and $687 ($501-1207) per incremental patient initiating tuberculosis treatment within 14 days. Cost-effectiveness was reduced in sites performing fewer than 150-250 tests annually.InterpretationThe XPEL-TB strategy facilitated higher rates of Xpert testing for tuberculosis at a similar per-test cost and modest incremental cost per tuberculosis diagnosis and treatment initiation. Decentralised Xpert testing, with appropriate implementation supports, should be scaled up to clinics with sufficient testing volume to support a single-module device.FundingThe National Heart, Lung, and Blood Institute.

The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false-negative viral PCR test results. Such tests are also susceptible to false-positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses, and nonviral conditions (n = 318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to diagnose COVID-19. We find that optimal classifiers include an interferon-stimulated gene that is strongly induced in COVID-19 compared with nonviral conditions, such as IFI6, and a second immune-response gene that is more strongly induced in other viral infections, such as GBP5. The IFI6+GBP5 classifier achieves an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort (n = 553). We further provide proof-of-concept demonstration that the classifier can be implemented in a clinically relevant RT-qPCR assay. Finally, we show that its performance is robust across common SARS-CoV-2 variants and is unaffected by cross-contamination, demonstrating its utility for improved accuracy of COVID-19 diagnostics. IMPORTANCE In this work, we study upper respiratory tract gene expression to develop and validate a 2-gene host-based COVID-19 diagnostic classifier and then demonstrate its implementation in a clinically practical qPCR assay. We find that the host classifier has utility for mitigating false-negative results, for example due to SARS-CoV-2 variants harboring mutations at primer target sites, and for mitigating false-positive viral PCR results due to laboratory cross-contamination. Both types of error carry serious consequences of either unrecognized viral transmission or unnecessary isolation and contact tracing. This work is directly relevant to the ongoing COVID-19 pandemic given the continued emergence of viral variants and the continued challenges of false-positive PCR assays. It also suggests the feasibility of pan-respiratory virus host-based diagnostics that would have value in congregate settings, such as hospitals and nursing homes, where unrecognized respiratory viral transmission is of particular concern.

BackgroundStool is a potential sample for diagnosing Mycobacterium tuberculosis (Mtb) in patients with difficulty in expectorating. However, high mycobacterial culture contamination rates and Xpert MTB/RIF Ultra test error rates on stool samples have limited its use. OMNIgene SPUTUM (OM-S) is a sample transport reagent with characteristics of sputum decontamination while maintaining viable Mtb. We evaluated the impact of OM-S on Mtb diagnostic yield from stool using smear microscopy, Xpert MTB/RIF Ultra, and culture among presumptive TB patients.MethodsPaired stool and expectorated sputum samples were collected from consecutive Ugandan adults undergoing diagnostic evaluation for pulmonary TB between June 2018 and June 2019. Stool was divided into 2 portions: one was homogenized in OM-S (OM-S stool) and the other in PBS (PBS stool) as control. Both sputum and processed stool were tested for Mtb using concentrated smear fluorescence microscopy (CFM), Xpert MTB/RIF Ultra (Xpert) and Mycobacteria Growth Indicator Tube (MGIT) culture. Sensitivity, specificity, and predictive values for each test were calculated against sputum MGIT culture as the reference standard.ResultsOf the 200 participants, 120 (60%) were male, 73 (37%) were HIV positive (median CD4 120 cells/uL (IQR 43-297)) and 128 (64%) had confirmed pulmonary TB by sputum MGIT culture. Seven (4%) OM-S stool Xpert samples reported errors while 47 (25%) and 103 (61%) were contaminated on OM-S stool MGIT and PBS stool MGIT, respectively. OM-S stool MGIT was able to accurately diagnose 56 of the contaminated PBS stool MGIT samples compared to only 5 of the contaminated OM-S stool MGIT samples diagnosed by PBS stool MGIT. Sensitivity (95% Confidence Interval, CI) 89% (83-94) for OM-S stool Xpert was higher compared to that of OM-S stool MGIT 60% (51-69) and PBS stool MGIT 42% (32-52). Specificity (95%CI) 91% (82-97) was also higher for OM-S stool Xpert compared to OM-S stool MGIT 64% (51-75) and PBS stool MGIT 26% (16-38).ConclusionStool processed with OM-S showed potential to improve Mtb diagnostic yield and reduce rates of indeterminate results when tested on Xpert and MGIT culture. The method may thus be of value in Mtb detection among patients with difficulty to expectorate.

COVID-19 oral treatments require initiation within 5 days of symptom onset. Although antigen tests are less sensitive than RT-PCR, rapid results could facilitate entry to treatment. We collected anterior nasal swabs for BinaxNOW and RT-PCR testing and clinical data at a walk-up, community site in San Francisco, California between January and June 2022. SARS-CoV-2 genomic sequences were generated from positive samples and classified according to subtype and variant. Monte Carlo simulations were conducted to estimate the expected proportion of SARS-CoV-2 infected persons who would have been diagnosed within 5 days of symptom onset using RT-PCR versus BinaxNOW testing. Among 25,309 persons tested with BinaxNOW, 2,799 had concomitant RT-PCR. 1137/2799 (40.6%) were SARS-CoV-2 RT-PCR positive. We identified waves of predominant omicron BA.1, BA.2, BA.2.12, BA.4, and BA.5 among 720 sequenced samples. Among 1,137 RT-PCR positive samples, 788/1137 (69%) were detected by BinaxNOW; 94% (669/711) of those with Ct value

High rates of new cervical cancer cases and deaths occur in low- and middle-income countries yearly, and one reason was found related to limitation of regular cervical cancer screening in local and low-resource settings. HPV has over 150 types, yet certain 14-20 high-risk and 13-14 low-risk types are common, and, thus, most conventional HPV nucleic acid assays, for examples, Cobas 4800 HPV test (Roche Diagnostics, New Jersey, USA) and REBA HPV-ID (Molecules and Diagnostics, Wonju, Republic of Korea) were developed to cover these types. We thereby utilized bioinformatics combined with recent isothermal amplification technique at 35-42 °C to firstly describe multiplex recombinase polymerase amplification assay that is specific to these common 20 high-risk and 14 low-risk types, and also L1 and E6/E7 genes that target different stages of cervical cancer development. Multiplex primer concentrations and reaction incubation conditions were optimized to allow simultaneous two gene detections at limit of detection of 1000 copies (equivalent to 2.01 fg) for L1 and 100 copies (0.0125 fg) for E6/E7, respectively. The assay was validated against urogenital and other pathogens, normal flora, and human control. In 130 real clinical sample tests, the assay demonstrated 100% specificity, 78% diagnostic accuracy, and 75% sensitivity compared with REBA HPV-ID test, and is much more rapid (15-40 min), less expensive (~ 3-4 USD/reaction) and does not require instrumentation (35-42 °C reaction condition so hand holding or tropical temperature is possible). Hence, the developed novel assay provides alternative screening tool for potential local screening. Furthermore, as this assay uses safe chemical reagents, it is safe for users.

BACKGROUND: The current version of the Fetal Medicine Foundation competing risks model for preeclampsia prediction has not been previously validated in Brazil. OBJECTIVE: This study aimed (1) to validate the Fetal Medicine Foundation combined algorithm for the prediction of preterm preeclampsia in the Brazilian population and (2) to describe the accuracy and calibration of the Fetal Medicine Foundation algorithm when considering the prophylactic use of aspirin by clinical criteria. STUDY DESIGN: This was a cohort study, including consecutive singleton pregnancies undergoing preeclampsia screening at 11 to 14 weeks of gestation, examining maternal characteristics, medical history, and biophysical markers between October 2010 and December 2018 in a university hospital in Brazil. Risks were calculated using the 2018 version of the algorithm available on the Fetal Medicine Foundation website, and cases were classified as low or high risk using a cutoff of 1/100 to evaluate predictive performance. Expected and observed cases with preeclampsia according to the Fetal Medicine Foundation–estimated risk range (≥1 in 10; 1 in 11 to 1 in 50; 1 in 51 to 1 in 100; 1 in 101 to 1 in 150; and

Background: Leptospirosis is an underdiagnosed infectious disease with non-specific clinical presentation that requires laboratory confirmation for diagnosis. The serologic reference standard remains the microscopic agglutination test (MAT) on paired serum samples. However, reported estimates of MAT's sensitivity vary. We evaluated the accuracy of four index tests, MAT on paired samples as well as alternative standards for leptospirosis diagnosis: MAT on single acute-phase samples, polymerase chain reaction (PCR) with the target gene Lfb1, and ELISA IgM with Leptospira fainei serovar Hurstbridge as an antigen. Methods: We performed a systematic review of studies reporting results of leptospirosis diagnostic tests. We searched eight electronic databases and selected studies that tested human blood samples and compared index tests with blood culture and/or PCR and/or MAT (comparator tests). For MAT selection criteria we defined a threshold for single acute-phase samples according to a national classification of leptospirosis endemicity. We used a Bayesian random-effect meta-analysis to estimate the sensitivity and specificity of MAT in single acute-phase and paired samples separately, and assessed risk of bias using the Quality Assessment of Studies of Diagnostic Accuracy Approach- 2 (QUADAS-2) tool. Results: For the MAT accuracy evaluation, 15 studies were included, 11 with single acute-phase serum, and 12 with paired sera. Two included studies used PCR targeting the Lfb1 gene, and one included study used IgM ELISA with Leptospira fainei serovar Hurstbridge as antigen. For MAT in single acute-phase samples, the pooled sensitivity and specificity were 14% (95% credible interval [CrI] 3–38%) and 86% (95% CrI 59–96%), respectively, and the predicted sensitivity and specificity were 14% (95% CrI 0–90%) and 86% (95% CrI 9–100%). Among paired MAT samples, the pooled sensitivity and specificity were 68% (95% CrI 32–92%) and 75% (95% CrI 45–93%) respectively, and the predicted sensitivity and specificity were 69% (95% CrI 2–100%) and 75% (2–100%). Conclusions: Based on our analysis, the accuracy of MAT in paired samples was not high, but it remains the reference standard until a more accurate diagnostic test is developed. Future studies that include larger numbers of participants with paired samples will improve the certainty of accuracy estimates. [ABSTRACT FROM AUTHOR]

Background Recognition of acute diverticulitis is important to determine an adequate management strategy. Differentiating it from other gastrointestinal disorders is challenging as symptoms overlap. Clinical tests might assist the clinician with this diagnostic challenge. Previous reviews have focussed on prognostic questions and imaging examinations in secondary care. Objective To evaluate the diagnostic accuracy of clinical tests feasible in primary care for acute diverticulitis in suspected patients. Method We have systematically searched multiple databases for diagnostic accuracy studies of tests feasible in primary care compared to a reference standard in suspected patients. Two reviewers independently selected studies, extracted data, and assessed study quality with the QUADAS-2 tool. We have meta-analysed the results in the case of more than four studies per index test. Results Seventeen studies were included, all studies were performed in secondary care (median prevalence 48%). Individual signs and symptoms showed a wide range in sensitivity (range 0.00–0.98) and specificity (range 0.08–1.00). Of the four laboratory tests evaluated, CRP >10 mg/l had the highest sensitivity (range 0.89–0.96) with specificity ranging from 0.28 to 0.61. Ultrasound had the highest pooled sensitivity and specificity of 0.92 (95% CI 0.86–0.96) and 0.94 (95% CI 0.88–0.97), respectively. Conclusion None of the studies were performed in primary care. Individual signs and symptoms alone are insufficiently informative for acute diverticulitis diagnosis. CRP showed potential for ruling out and ultrasound had a high diagnostic accuracy. More research is needed about the diagnostic accuracy of these tests in primary care. PROSPERO registration number CRD42021230622 [ABSTRACT FROM AUTHOR]

We aimed to quantify the clinical utility of continuous performance tests (CPTs) for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) compared to a clinical diagnosis in children and adolescents. Four databases (MEDLINE, PsycINFO, EMBASE, and PubMed) were screened until January 2023. Risk of bias of included results was judged with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We statistically pooled the area under the curve, the sensitivity, and the specificity of 3 commonly used CPTs subscales: omission/inattention, commission/impulsivity, and total number of errors/ADHD subscales (PROSPERO registration: CRD42020168091). A total of 19 studies using commercially available CPTs were identified. Results from up to 835 control individuals and 819 cases were combined in the summary receiver operating characteristic (ROC) curve analyses (sensitivity and specificity pooling), and up to 996 cases and 1,083 control individuals in the area under the curve (AUC) analyses. Clinical utility as measured by AUCs could be considered as barely acceptable (between 0.7 and 0.8) for the most part, with the best results for the total/ADHD score, followed by omissions/inattention, and poorest for commission/impulsivity scores. A similar pattern was found when pooling sensitivity and specificity: 0.75 (95% CI = 0.66-0.82) and 0.71 (0.62-0.78) for the total/ADHD score; 0.63 (0.49-0.75) and 0.74 (0.65-0.81) for omissions; and 0.59 (0.38-0.77) and 0.66 (CI = 0.50-0.78) for commissions. At the clinical level, CPTs as a stand-alone tool have only a modest to moderate ability to differentiate ADHD from non-ADHD samples. Hence, they should be used only within a more comprehensive diagnostic process. A systematic review of screening tools for ADHD in children and adolescents; https://www.crd.york.ac.uk/prospero/ ; CRD42020168091. [ABSTRACT FROM AUTHOR]

Background: Pilot study showed that Alzheimer's disease resemblance atrophy index (AD-RAI), a machine learning-derived MRI-based neurodegeneration biomarker of AD, achieved excellent diagnostic performance in diagnosing AD with moderate to severe dementia. Objective: The primary objective was to validate and compare the performance of AD-RAI with conventional volumetric hippocampal measures in diagnosing AD with mild dementia. The secondary objectives were 1) to investigate the association between imaging biomarkers with age and gender among cognitively unimpaired (CU) participants; 2) to analyze whether the performance of differentiating AD with mild dementia from CU will improve after adjustment for age/gender. Methods: AD with mild dementia (n = 218) and CU (n = 1,060) participants from 4 databases were included. We investigated the area under curve (AUC), sensitivity, specificity, and balanced accuracy of AD-RAI, hippocampal volume (HV), and hippocampal fraction (HF) in differentiating between AD and CU participants. Among amyloid-negative CU participants, we further analyzed correlation between the biomarkers with age/gender. We also investigated whether adjustment for age/gender will affect performance. Results: The AUC of AD-RAI (0.93) was significantly higher than that of HV (0.89) and HF (0.89). Subgroup analysis among A + AD and A- CU showed that AUC of AD-RAI (0.97) was also higher than HV (0.94) and HF (0.93). Diagnostic performance of AD-RAI and HF was not affected by age/gender while that of HV improved after age adjustment. Conclusions: AD-RAI achieves excellent clinical validity and outperforms conventional volumetric hippocampal measures in aiding the diagnosis of AD mild dementia without the need for age adjustment. [ABSTRACT FROM AUTHOR]

Objectives: To correlate the screening ability of ultrasound-based TIRADS with the FNAC-based Bethesda system when the latter is kept as a gold standard. Material and methods: A cross-sectional study was conducted in the Histopathology department, Rehman Medical Institute, Peshawar 15th June 2022-14th June 2023. A total of 363 patients from any age group of either gender diagnosed with thyroid nodules were included in the trial. All the participants underwent ultrasound followed by ultrasound-guided fine needle aspiration of thyroid nodules. TIRADS and Bethesda grading was done for each participant. Demographics and grading scores were recorded. Keeping Bethesda scoring as gold standard diagnostic performance of TIRADS grading was calculated. Results: Mean age of the patients was 46.68 ± 12.28 years with a female-to-male ratio of 2.3:1. TIRADS grading revealed 210 (69.8%) from TIRADS 2 while 70(82.4%), 12(50%), and 09(23.7%) patients were from TIRADS 3, 4 and 5 categories respectively. Bethesda grades were 301(82.9%), 21(5.8%), 09(2.5%), 28(7.7%), and 04(1.1%) from Bethesda 2, 3, 4, 5, and 6 categories respectively. The sensitivity of the TIRADS was 93.8%, specificity 89.1%, positive predictive value 45%, negative predictive value 99.3%, and a diagnostic accuracy of 89.5%. Conclusion: TIRADS grading has a high diagnostic ability when Bethesda scoring is kept as the gold standard. It can be used effectively in segregating benign from malignant nodules and is recommended for screening patients presenting with thyroid nodules. [ABSTRACT FROM AUTHOR]

The present study assessed the diagnostic performance of the Xpert®Xpress SARS-CoV-2 test in comparison with the Charité protocol real-time RT PCR for the detection of SARS-CoV-2 in Peruvian patients. This was a diagnostic test study that included 100 nasal and pharyngeal swab samples. We obtained an overall concordance of 98.70% (95%CI: 92.98-99.97), with a kappa coefficient of 0.97 (95%CI: 0.86-1.00) and sensitivity and relative specificity rates of 100% and 96.15%, respectively. Additionally, the percentage of the area under the ROC curve was 98.08% in both cases, and an analytical specificity rate of 100% was obtained for the different respiratory viruses evaluated. In conclusion, the Xpert®Xpress SARS-CoV-2 test, by using nasal and pharyngeal swab samples, was highly sensitive and specific, and the kappa coefficient showed an excellent correlation when compared to the reference test. [ABSTRACT FROM AUTHOR]

Background Gestational Diabetes causes several maternal and fetal complications. Recognizing and treating diabetes or any degree of glucose intolerance in pregnancy results in lowering maternal and fetal complications. DIPSI (recommended by FOGSI and validated by MoHFW, India) suggesteda single step testing for GDM. Several studies done in India and abroad have suggested conflicting results as compared to the standard IADPSG 75 gm OGTT. This study compares the efficacy of the sensitivity and specificity of DIPSI OGTT as against gold standard IADPSG OGTT criteria. Material and Method A prospective Diagnostic Evaluation Study carried out on 450 Antenatal patients at a zonal hospital in Eastern India. All participants were subjected to OGTT test by both IADPSG& DIPSI criteria on two separate occasions 7 days apart in the 1st trimester as well as between 24 to 28 weeks.DIPSI results were compared between 75 patients who were positive & 75 patients who were negative by IADPSG criteria. Sensitivity and specificity were calculated. Results Sensitivity and Specificity of DIPSI OGTT as against IADPSG OGTT was found to be 90% and 100% respectively. Conclusion The best approach to screen for Gestational Diabetes is undoubtedly the IADPSG Criteria as recommended by WHO. However in resource poor and developing countries like India, DIPSI criteria is also a good alternative to the IADPSG criteria. Larger multicentric multinational studies are required to establish the diagnostic efficacy of DIPSI as an equally efficacious alternative to the standard IADPSG OGTT. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the association between depression and self-care in diabetic patients potentially influenced by biases in depression measurement using weighting the positive and negative predictive values. Methods: In this cross-sectional study, 1050 patients informedly consented to participate in the study. Using a WHO-5 well-being index, the participants were examined for depressive mood as exposure. The sensitivity and specificity of this index in a systematic review study were 0.86 and 0.81, respectively. Self-care (that is outcome) was assessed using the Summary of Diabetes Self-Care Activities (SDSCA) questionnaire. To correct the misclassification bias of exposure, the predictive weighting method was used in the multivariable logistic regression model adjusted for covariates. Bootstrap sample with replacement and simulation was used to deal with random error. Results: The mean age of patients was 42.8 ± 7.5 years. In this study, 70.1% of diabetic patients (n = 720) were depressed based on the questionnaire score and only 52.7% (n = 541) of them had appropriate self-care behaviors. Our study revealed a close relationship between self-care and covariates such as gender, depression, having comorbidities, abdominal obesity, economic status and education. The odds ratio of the association between depressive mood and lack of self-care in primary multivariable logistic regression was 2.21 (95% CI: 1.62-3.00, p < 0.001) and after misclassification bias adjusting, it was equal to 3.4 (95% CI: 1.7–6.6, p < 0.001). The OR percentage of bias was − 0.55. Conclusion: After adjusting for depression misclassification bias and random error, the observed association between depression and self-care was stronger. According to our findings, psychiatric interventions, and counseling and education along with self-care interventions are necessary for these patients. Special attention should be paid to male, low economic classes, less educated and those having a history of comorbidities along with psychological assessment when improving the care and progress of treatment in diabetic patients is expected. Future studies are needed to clarify the role of other psychological disorders on self-care of diabetics. [ABSTRACT FROM AUTHOR]

Background: The sensitivity of HIV screening assays often leads to a high rate of false-positive results, requiring retests and confirmatory tests. This study aimed to analyze the capability of signal-to-cutoff (S/CO) ratios of HIV screening assay to predict HIV infection. Methods: A retrospective study on the HIV screening-positive population was performed at Zhongshan Hospital, Xiamen University, the correlation between HIV screening assay S/CO ratios and HIV infection was assessed, and plotted Receiver Operating Characteristic (ROC) curves were generated to establish the optimal cutoff value for predicting HIV infection. Results: Out of 396,679 patients, 836 were confirmed to be HIV-infected, with an HIV prevalence of 0.21%. The median S/CO ratios in HIV infection were significantly higher than that in non-HIV infection (296.9 vs. 2.41, P < 0.001). The rate of confirmed HIV infection was increased with higher S/CO ratios in the screening assay. The ROC curve based on the HIV screening assay S/CO ratio achieved a sensitivity of 93.78% and a specificity of 93.12% with an optimal cutoff value of 14.09. The area under the ROC curve was 0.9612. Further analysis of the ROC curve indicated that the S/CO ratio thresholds yielding positive predictive values of 99%, 99.5%, and 100% for HIV infection were 26.25, 285.7, and 354.5, respectively. Conclusion: Using HIV screening assay S/CO ratio to predict HIV infection can largely reduce necessitating retests and confirmatory tests. Incorporating the S/CO ratio into HIV testing algorithms can have significant implications for medical and public health practices. [ABSTRACT FROM AUTHOR]