CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT.

BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.

A prospective evaluation of the diagnostic accuracy of the point-of-care VISITECT CD4 Advanced Disease test in seven countries.

BACKGROUND: CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT® CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or >200 cells/µl from finger-prick or venous blood. METHODS: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated. RESULTS: Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128-626) cells/µl and 521 (32.5%) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7% (483/521, 95% CI 90.1-94.7%) and specificity was 61.4% (665/1083, 95% CI 58.4-64.3%). For participants with a CD4 between 0-100, 101-200, 201-300, 301-500, and >500 cells/µl, VISITECT misclassified 4.5% (95% CI 2.5-7.2%), 12.5 (95% CI 8.0-18.2%), 74.1% (95% CI 67.0-80.5%), 48.0% (95% CI 42.5-53.6%), and 22.6% (95% CI 19.3-26.3%), respectively. CONCLUSIONS: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated.

Performance of HCV core antigen and PCR testing in a predominantly genotype 3 population.

Hepatitis C core antigen (HCVcAg) is becoming increasingly recognized as an alternative to molecular testing for the confirmation of chronic hepatitis C. However, there are limited data on the performance of this assay in a genotype 3 (GT3) predominant country like Pakistan. We conducted a study to evaluate the diagnostic performance of HCVcAg against the HCV polymerase chain reaction (PCR) molecular test. HCV antibody-positive patients requiring confirmatory testing were recruited from August to October 2018 at the Pakistan Kidney and Liver Institute and Research Center (PKLI&RC), Lahore, Pakistan. Patients with previously known diagnoses or treatment histories were excluded. The Abbott HCV Ag assay was used for HCVcAg testing. Results ≥3.00 fmol/L were considered positive for HCVcAg. The Abbott RealTime HCV assay was used for PCR testing with a lower detection limit of ≥12 IU/mL. We computed the sensitivity, specificity and correlation of HCVcAg against HCV PCR. A total of 394 patients were recruited. The median age of the patients was 42 years. Most participants were females (51.5%, n = 203), 30.7% (n = 121) had HTN, 10.4% DM (n = 41) and 5% had APRI ≥2. The overall sensitivity was 98.0% and the specificity was 98.6%. The lowest detection limit of cAg was an HCV RNA value of 4657 IU/mL. The levels of cAg were highly correlated with those of HCV RNA by Spearman's rank correlation test (r = 0.935, p < .001). HCVcAg represents a suitable alternative with high sensitivity and specificity compared with HCV PCR in the GT3-predominant population and can be incorporated into algorithms to improve linkage to care.

Introduction of a nationwide first-trimester anomaly scan in the Dutch national screening program.

BACKGROUND: A significant proportion of major fetal structural anomalies can be detected in the first trimester by ultrasound examination. However, the test performance of the first-trimester anomaly scan (FTAS) performed in a low-risk population as part of a nationwide prenatal screening program is unknown. Potential benefits of the FTAS include early detection of fetal anomalies, providing parents with more time for reproductive decision-making. OBJECTIVES: To investigate the uptake, test performance and time to a final prenatal diagnosis after referral. STUDY DESIGN: A nationwide implementation study was conducted in the Netherlands (November 2021-November 2022). The FTAS was performed between 12+3 and 14+3 weeks gestation by certified sonographers using a standard protocol. Women were referred to a tertiary care center if anomalies were suspected. Uptake, test performance and time to a final prenatal diagnosis (days between referral and date of final diagnosis/prognosis for reproductive decision-making) were determined. Test performance was calculated for first-trimester major congenital anomalies, such as anencephaly and holoprosencephaly and all diagnosed anomalies <24 weeks gestation. RESULTS: The FTAS uptake was 74.9% (129 704/173 129). In 1.0% (1 313/129 704), an anomaly was suspected, of which 54.9% (n=721) had abnormal findings on the detailed first-trimester diagnostic scan and 44.6% (n=586) showed normal results. In 0.5% (n=6), intra-uterine fetal death occurred. In the total group of 721 cases with abnormal findings, 332 structural anomalies, 117 genetic anomalies, 82 other findings (abnormal fetal biometry, sonomarkers, placental/umbilical cord anomaly, an-/oligohydramnios) and 189 cases with transient findings (defined as ultrasound findings which resolved <24 weeks gestation) were found, with one case having an unknown outcome. 0.9% (n=1164) of all cases with a normal FTAS were diagnosed with a fetal anomaly in the second trimester. Test performance included a sensitivity of 84.6% (126/149) for first-trimester major congenital anomalies and 31.6% (537/1701) for all types of anomalies. Specificity for all anomalies was 99.2% (98 055/98 830); positive predictive value 40.9% (537/1 312); negative predictive value 98.8% (98 055/99 219); positive likelihood ratio 40.3; negative likelihood ratio 0.7; false positive rate 0.8% (775/98 830) and false negative rate 68.4% (1 164/1 701). The median time to diagnosis for structural anomalies was 20 days (6-43 days; median GA 16+3), for genetic anomalies 17 days (8.5-27.5 days; median GA 15+6 weeks) and for first-trimester major congenital anomalies 9 days (5-22 days; median GA 14+6 weeks). CONCLUSIONS: The performance of a newly introduced nationwide FTAS in a low-risk population showed a high sensitivity for first-trimester major congenital anomalies and a lower sensitivity for all anomalies combined. The program was accompanied by a referral rate of 1.0%, of which 59.1% involved cases where anomalies were either not confirmed or resolved before 24 weeks gestation. Timing of diagnosis was around 16 weeks gestation for referred cases. To evaluate the balance between benefits and potential harm of the FTAS within a nationwide prenatal screening program, it is essential to assess the effectiveness of the program over time and to consider the perspectives of both women and their partners, as well as healthcare professionals.

Automated ASPECTS calculation may equal the performance of experienced clinicians: a machine learning study based on a large cohort.

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.

Diagnostic ability of [18F]FDG PET/CT for distinguishing benign from malignant spleen lesions.

OBJECTIVES: [18F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is a non-invasive imaging modality used in the differential diagnosis of splenic lesions, although ideal parameters and thresholds remain unclear. The present study evaluated the ability of [18F]FDG PET/CT, including its visual and quantitative parameters, to differentiate between benign and malignant splenic lesions. METHODS: Patients who underwent [18F]FDG PET/CT following the detection of splenic lesions on contrast-enhanced CT were retrospectively analysed. Visual parameters assessed on [18F]FDG PET/CT included whole spleen uptake intensity, lesion multiplicity, and lesion uptake, and quantitative parameters included maximum standardised uptake value (SUVmax), lesion-to-background ratio (LBR), metabolic tumour volume (MTV), total lesion glycolysis (TLG), and lesion size. Parameters differentiating between benign and malignant lesions were evaluated by Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristics (ROC) curve analysis. RESULTS: Splenic lesion uptake (p = 0.001) was the only visual parameter significantly distinguishing between benign and malignant lesions. ROC curve analysis demonstrated that SUVmax had the largest area under the ROC, 0.91 (p < 0.001), with an optimal cut-off > 5.3 having a sensitivity of 90.3% and a specificity of 80.6%. Subgroup analysis of malignant lesions showed that SUVmax (p = 0.013), LBR (p = 0.012), and TLG (p = 0.034) were significantly higher in splenic lymphomas than in splenic metastases. CONCLUSION: Of the [18F]FDG PET/CT parameters investigated, SUVmax had the highest accuracy in diagnosing malignant splenic lesions and was significantly higher in splenic lymphomas than in splenic metastases. Visual determination of [18F]FDG uptake by splenic lesions may be an easily evaluated parameter. CLINICAL RELEVANCE STATEMENT: SUVmax and visual grade of [18F]FDG PET/CT help to differentiate spleen lesions. [18F]FDG PET/CT is useful for discriminating between benign and malignant spleen lesions. KEY POINTS: Many splenic lesions are difficult to diagnose on anatomical imaging, with histopathologic analyses are required. SUVmax of PET/CT provided the diagnostic ability to differentiate between benign and malignant splenic lesions. More than normal spleen uptake can be a convenient parameter to diagnose malignant spleen lesions.

Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

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.

Understanding the biases to sepsis surveillance and quality assurance caused by inaccurate coding in administrative health data.

PURPOSE: Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. METHODS: We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015-2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. RESULTS: ICD-coding of sepsis in IAHD showed high positive predictive value (76.9-85.7% depending on sepsis definition), but low sensitivity (26.8-38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29-71.7%, of ICD-diagnosis: 10.7-58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). CONCLUSION: Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care.

Diagnosis of human leptospirosis: systematic review and meta-analysis of the diagnostic accuracy of the Leptospira microscopic agglutination test, PCR targeting Lfb1, and IgM ELISA to Leptospira fainei serovar Hurstbridge.

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.

Accuracy of diagnostic tests for acute diverticulitis that are feasible in primary care: a systematic review and meta-analysis.

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.

Diagnostic performance of the CellaVision preclassification neutrophil count - time to bypass the reclassification?

OBJECTIVES: The objective of this study was to perform a method comparison between the CellaVision preclassification neutrophil count and the reclassification neutrophil count performed by trained laboratory technicians, and to evaluate the diagnostic performance of the preclassification neutrophil count at clinical decision levels. METHODS: We retrospectively identified patient samples through 2019-2022 in which the differential count was performed on Cellavision (n = 4,354). Data on sample characteristics and leukocyte- and differential counts was extracted from the electronic medical journal. For each sample, data containing the pre- and reclassification leukocyte classification, respectively, was extracted from the Cellavision software. Method comparison between the pre-and reclassification neutrophil count was performed using Bland Altman analysis. Diagnostic performance of the preclassification neutrophil count was evaluated according to four pre-specified categories of results with the reclassification as reference method. RESULTS: The median difference between the pre- and reclassification neutrophil count was 0.044 x 109/L. The preclassification neutrophil count categorised 95.6% of all samples correctly according to the four categories. The sensitivity, specificity, positive predictive value and negative predictive value for detecting neutrophilia > 7.00 x 109/L was 98.8%, 97.2%, 95.8%, and 99.2%, respectively. In samples with leukopenia (n = 543), the sensitivity, specificity, positive predictive value and negative predictive value for detecting severe neutropenia (< 0.50 x 109/L) was 97.7%, 99.1%, 98.6%, and 98.5%, respectively. CONCLUSION: The diagnostic performance of the CellaVision preclassification neutrophil count was satisfactory. The preclassification neutrophil count may be released to the electronic medical journal to improve turnaround time and benefit laboratory management.

Diagnostic accuracy, reliability, and construct validity of the German quick mild cognitive impairment screen.

BACKGROUND: Early detection of cognitive impairment is among the top research priorities aimed at reducing the global burden of dementia. Currently used screening tools have high sensitivity but lack specificity at their original cut-off, while decreasing the cut-off was repeatedly shown to improve specificity, but at the cost of lower sensitivity. In 2012, a new screening tool was introduced that aims to overcome these limitations - the Quick mild cognitive impairment screen (Qmci). The original English Qmci has been rigorously validated and demonstrated high diagnostic accuracy with both good sensitivity and specificity. We aimed to determine the optimal cut-off value for the German Qmci, and evaluate its diagnostic accuracy, reliability (internal consistency) and construct validity. METHODS: We retrospectively analyzed data from healthy older adults (HOA; n = 43) and individuals who have a clinical diagnosis of 'mild neurocognitive disorder' (mNCD; n = 37) with a biomarker supported characterization of the etiology of mNCD of three studies of the 'Brain-IT' project. Using Youden's Index, we calculated the optimal cut-off score to distinguish between HOA and mNCD. Receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic accuracy based on the area under the curve (AUC). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Reliability (internal consistency) was analyzed by calculating Cronbach's α. Construct validity was assessed by analyzing convergent validity between Qmci-G subdomain scores and reference assessments measuring the same neurocognitive domain. RESULTS: The optimal cut-off score for the Qmci-G was ≤ 67 (AUC = 0.96). This provided a sensitivity of 91.9% and a specificity of 90.7%. The PPV and NPV were 89.5% and 92.9%, respectively. Cronbach's α of the Qmci-G was 0.71 (CI95% [0.65 to 0.78]). The Qmci-G demonstrated good construct validity for subtests measuring learning and memory. Subtests that measure executive functioning and/or visuo-spatial skills showed mixed findings and/or did not correlate as strongly as expected with reference assessments. CONCLUSION: Our findings corroborate the existing evidence of the Qmci's good diagnostic accuracy, reliability, and construct validity. Additionally, the Qmci shows potential in resolving the limitations of commonly used screening tools, such as the Montreal Cognitive Assessment. To verify these findings for the Qmci-G, testing in clinical environments and/or primary health care and direct comparisons with standard screening tools utilized in these settings are warranted.

The Role of Ultrasound Semi-Quantitative Scoring in the Diagnosis and Assessment of Gout and Hyperuricemia.

OBJECTIVES: To develop an ultrasound semi-quantitative scoring system for the diagnosis and evaluation of gout and hyperuricemia. METHODS: This study included 348 male patients: 81 patients with asymptomatic hyperuricemia, 182 patients with gout, and 85 patients with other arthritis. Clinical data were collected, ultrasound was detected, gout activity score was calculated to assess disease activity, and statistical analysis was performed. RESULTS: Monosodium urate crystal deposition and subclinical arthritis were detected in 17 patients with asymptomatic hyperuricemia, with lesions concentrated in the metatarsophalangeal joint, ankle and peroneus-longus and brevis at rate of 91.8%. Gout was significantly higher than non-gouty arthritis in crystal scores (sum scores of double contour, aggregates, and tophi), but not in inflammation scores (sum scores of synovial hypertrophy, power Doppler [PD] activity, and tenosynovitis) and bone erosion. The optimal cut-off score for the diagnosis of gout by the crystal score was 2. The sensitivity, specificity, and AUC were 95.4%, 97.1%, and .965, respectively. Gout flare had higher inflammation scores than intercritical gout, while bone erosion scores were lower than intercritical gout. The active gout patients had higher ultrasound scores of tophi, bone erosion, and PD activity than the remission group (P < .001). The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) for the identification with high disease activity gout by ultrasound semi-quantitative composite score were 76.2%, 84.2%, and .812, respectively. CONCLUSION: Ultrasound helps early identification of patients at risk in asymptomatic hyperuricemia. Ultrasound semi-quantitative scoring allows for more objective and accurate assessment of gout lesions, correlates with disease activity, and helps in the diagnosis and assessment of gout.

Acipenserid herpesvirus 2 genome and partial validation of a qPCR for its detection in white sturgeon Acipenser transmontanus.

White sturgeon Acipenser transmontanus is the primary species used for caviar and sturgeon meat production in the USA. An important pathogen of white sturgeon is acipenserid herpesvirus 2 (AciHV-2). In this study, 4 archived isolates from temporally discrete natural outbreaks spanning the past 30 yr were sequenced via Illumina and Oxford Nanopore Technologies platforms. Assemblies of approximately 134 kb were obtained for each isolate, and the putative ATPase subunit of the terminase gene was selected as a potential quantitative PCR (qPCR) target based on sequence conservation among AciHV-2 isolates and low sequence homology with other important viral pathogens. The qPCR was repeatable and reproducible, with a linear dynamic range covering 5 orders of magnitude, an efficiency of approximately 96%, an R2 of 0.9872, and an analytical sensitivity of 103 copies per reaction after 35 cycles. There was no cross-reaction with other known viruses or closely related sturgeon species, and no inhibition by sturgeon DNA. Clinical accuracy was assessed from white sturgeon juveniles exposed to AciHV-2 by immersion. Viral culture (gold standard) and qPCR were in complete agreement for both cell culture negative and cell culture positive samples, indicating that this assay has 100% relative accuracy compared to cell culture during an active outbreak. The availability of a whole-genome sequence for AciHV-2 and a highly specific and sensitive qPCR assay for detection of AciHV-2 in white sturgeon lays a foundation for further studies on host-pathogen interactions while providing a specific and rapid test for AciHV-2 in captive and wild populations.

Accuracy of contrast-enhanced CT in liver neoplasms in children under 2 years age.

BACKGROUND: Multiple differentials exist for pediatric liver tumors under 2 years. Accurate imaging diagnosis may obviate the need for tissue sampling in most cases. OBJECTIVE: To evaluate the imaging features and diagnostic accuracy of computed tomography (CT) in liver tumors in children under 2 years. METHODS: Eighty-eight children under 2 years with treatment naive liver neoplasms and baseline contrast-enhanced CT were included in this institutional review board approved retrospective study. Two blinded onco-radiologists assessed these tumors in consensus. Findings assessed included enhancement pattern, lobulated appearance, cystic change, calcifications, central scar-like appearance, and metastases. The radiologists classified the lesion as hepatoblastoma, infantile hemangioma, mesenchymal hamartoma, rhabdoid tumor, or indeterminate, first based purely on imaging and then after alpha-fetoprotein (AFP) correlation. Multivariate analysis and methods of comparing means and frequencies were used for statistical analysis wherever applicable. Diagnostic accuracy, sensitivity, and positive predictive values were analyzed. RESULTS: The mean age of the sample was 11.4 months (95% CI, 10.9-11.8) with 50/88 (57%) boys. The study included 72 hepatoblastomas, 6 hemangiomas, 4 mesenchymal hamartomas, and 6 rhabdoid tumors. Presence of calcifications, multilobular pattern of arterial enhancement, lobulated morphology, and central scar-like appearance was significantly associated with hepatoblastomas (P-value < 0.05). Fourteen out of eighty-eight lesions were called indeterminate based on imaging alone; six lesions remained indeterminate after AFP correlation. Pure radiology-based diagnostic accuracy was 81.8% (95% CI, 72.2-89.2%), which increased to 92.1% (95% CI, 84.3-96.7%) (P-value > 0.05) after AFP correlation, with one hepatoblastoma misdiagnosed as a rhabdoid tumor. If indeterminate lesions were excluded for biopsy, the accuracy would be 98.8% (95% CI, 93.4-99.9%). CONCLUSION: CT had high accuracy for diagnosing liver neoplasms in the under 2-year age population after AFP correlation. Certain imaging features were significantly associated with the diagnosis of hepatoblastoma. A policy of biopsying only indeterminate lesions after CT and AFP correlation would avoid sampling in the majority of patients.

Bias in vaccine effectiveness studies of clinically severe outcomes that are measured with low specificity: the example of COVID-19-related hospitalisation.

Many vaccine effectiveness (VE) analyses of severe disease outcomes such as hospitalisation and death include 'false' cases that are not actually caused by the infection or disease under study. While the inclusion of such false cases inflate outcome rates in both vaccinated and unvaccinated populations, it is less obvious how they affect estimates of VE. Illustrating the main points through simple examples, this article shows how VE is underestimated when false cases are included as outcomes. Depending how the outcome indicator is defined, estimates of VE against severe disease outcomes, whose definition allows for the inclusion of false cases, will be biased downwards and may in certain circumstances approximate the same level as the VE against infection. The bias is particularly pronounced for vaccines that offer high levels of protection against severe disease outcomes but poor protection against infection. Analysing outcomes that are measured with low sensitivity generally does not cause bias in VE studies; defining outcome indicators that minimise the number of false cases rather than the number of missed cases is preferable in VE studies.

Acute clinical evaluation for the diagnosis of lateral ankle ligament injuries is useful: A comparison between the acute and delayed settings.

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.

Identifying early language predictors: A replication of Gasparini et al. (2023) confirming applicability in a general population cohort.

BACKGROUND: Identifying language disorders earlier can help children receive the support needed to improve developmental outcomes and quality of life. Despite the prevalence and impacts of persistent language disorder, there are surprisingly no robust predictor tools available. This makes it difficult for researchers to recruit young children into early intervention trials, which in turn impedes advances in providing effective early interventions to children who need it. AIMS: To validate externally a predictor set of six variables previously identified to be predictive of language at 11 years of age, using data from the Longitudinal Study of Australian Children (LSAC) birth cohort. Also, to examine whether additional LSAC variables arose as predictive of language outcome. METHODS & PROCEDURES: A total of 5107 children were recruited to LSAC with developmental measures collected from 0 to 3 years. At 11-12 years, children completed the Clinical Evaluation of Language Fundamentals, 4th Edition, Recalling Sentences subtest. We used SuperLearner to estimate the accuracy of six previously identified parent-reported variables from ages 2-3 years in predicting low language (sentence recall score ≥ 1.5 SD below the mean) at 11-12 years. Random forests were used to identify any additional variables predictive of language outcome. OUTCOMES & RESULTS: Complete data were available for 523 participants (52.20% girls), 27 (5.16%) of whom had a low language score. The six predictors yielded fair accuracy: 78% sensitivity (95% confidence interval (CI) = [58, 91]) and 71% specificity (95% CI = [67, 75]). These predictors relate to sentence complexity, vocabulary and behaviour. The random forests analysis identified similar predictors. CONCLUSIONS & IMPLICATIONS: We identified an ultra-short set of variables that predicts 11-12-year language outcome with 'fair' accuracy. In one of few replication studies of this scale in the field, these methods have now been conducted across two population-based cohorts, with consistent results. An imminent practical implication of these findings is using these predictors to aid recruitment into early language intervention studies. Future research can continue to refine the accuracy of early predictors to work towards earlier identification in a clinical context. WHAT THIS PAPER ADDS: What is already known on the subject There are no robust predictor sets of child language disorder despite its prevalence and far-reaching impacts. A previous study identified six variables collected at age 2-3 years that predicted 11-12-year language with 75% sensitivity and 81% specificity, which warranted replication in a separate cohort. What this study adds to the existing knowledge We used machine learning methods to identify a set of six questions asked at age 2-3 years with ≥ 71% sensitivity and specificity for predicting low language outcome at 11-12 years, now showing consistent results across two large-scale population-based cohort studies. What are the potential or clinical implications of this work? This predictor set is more accurate than existing feasible methods and can be translated into a low-resource and time-efficient recruitment tool for early language intervention studies, leading to improved clinical service provision for young children likely to have persisting language difficulties.

[Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease]. / Stellenwert von ASS-Provokationen beim Analgetika-Intoleranz-Syndrom.

BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by a severe course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on a plausible positive history of NSAID hypersensitivity and CRSwNP with asthma. OBJECTIVE: The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which a positive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. RESULTS AND CONCLUSION: ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is a high concordance between a positive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.

Validation and bifactor structure of the French Adult ADHD Symptoms Rating Scale v1.1 (ASRS).

BACKGROUND: Three scoring methods for the widely available Adult ADHD Symptoms Rating Scale v1.1 (ASRS) have been proposed to screen for ADHD, but these three methods have rarely been compared against formal clinical diagnoses. We aimed to validate the French version of the ASRS against a clinical interview using DSM-IV and DSM-5 diagnostic algorithms. METHODS: One hundred five adults from a convenience sample were evaluated with the ASRS and the DIVA 2.0, using both DSM-IV and DSM-5 criteria. We used Confirmatory Factor Analysis to investigate the underlying structure of the ASRS. Sensitivity, specificity, and classification accuracy were compared between the rating algorithms of the ASRS. RESULTS: The full score method had worse predictive performance than the Screener and the 2-stage scoring method. All characteristics of the three scoring methods for the ASRS were worse when applying DSM-5 criteria. The best-fitting structure was a bi-factor model with a general ADHD factor and three specific factors. CONCLUSIONS: ADHD was best conceived as a one-dimensional construct. The 2-stage scoring method superseded the Screener with comparable sensitivity and specificity.