Similar Specificity Research Articles

NIMG-74. A NOVEL APPROACH FOR PERSONALIZED RADIOTHERAPY TARGET VOLUME DEFINITION USING METABOLIC MRI AND DEEP LEARNING-DRIVEN PREDICTIONS OF GLIOBLASTOMA RECURRENCE

Abstract BACKGROUND Machine-learning models have demonstrated great promise in predicting tumor infiltration beyond anatomical margins in glioblastoma. Yet standard-of-care (SOC) radiation therapy (RT) planning only utilizes a uniform, isotropic 2cm-expansion of the T1-post-contrast-lesion or T2-lesion to generate a clinical target volume (CTV), without considering heterogeneity in tumor infiltration. We hypothesize that using a novel deep-learning approach to predict regions of tumor progression with metabolic and diffusion-weighted MRI will result in personalized CTVs that are more sensitive to detecting normal-appearing infiltrating tumor beyond the T2-lesion, sparing more healthy brain compared to SOC-CTVs. METHODS Anatomical, diffusion-weighted, and metabolic MRI from 101 patients with glioblastoma, acquired post-surgery but prior to chemoradiation, were retrospectively used to predict regions of new contrast-enhancement or T2-hyperintensity at confirmed progression. A segmentation-based predictive deep-learning approach with personalized loss-functions and evaluation metrics (“Progression-Coverage-Coefficient”, PCC) that weight Dice coefficient terms by tumor size was employed with a 66/17/18 train/validation/test split of patients and the resulting DL-CTV compared to two SOC-CTVs: 1) the RTOG[T2-FLAIR+2cm]-CTV, 2) the EORTC[T1c+2cm]-CTV. RESULTS Our best deep-learning-CTV trained using anatomical, diffusion, and metabolic MRI achieved significantly improved median test specificity (0.87 vs. 0.77; p<0.005) and comparable sensitivity (0.92 vs. 0.95; p=0.1) and PCC (0.81 vs. 0.79; p=0.1) to the SOC RTOG[T2-FLAIR+2cm]-CTV, sparing more normal brain tissue. Compared to the more conservative EORTC[T1c+2cm]-CTV, our approach had significantly higher test sensitivity (0.92 vs. 0.85; p<0.00001) and PCC (0.81 vs. 0.77; p=0.003) in covering the progressed lesion, while maintaining similar specificity (0.87 vs. 0.89; p=0.3). Test performance dropped by 9.6% and 12.4% when removing metabolic and both metabolic and diffusion metrics, respectively (p<0.001). CONCLUSION This study demonstrates the benefit of using metabolic and diffusion MRI with deep learning for personalized RT planning by targeting regions of anatomically normal infiltrative disease that are highly likely to progress, while reducing treatment to normal brain.

Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families.

Mirror-Image Random Nonstandard Peptides Integrated Discovery (MI-RaPID) Technology Yields Highly Stable and Selective Macrocyclic Peptide Inhibitors for Matrix Metallopeptidase 7.

Matrix metallopeptidase 7 (MMP7) plays a crucial role in cancer metastasis and progression, making it an attractive target for therapeutic development. However, the development of selective MMP7 inhibitors is challenging due to the conservation of active sites across various matrix metalloproteinases (MMPs). Here, we have developed mirror-image random nonstandard peptides integrated discovery (MI-RaPID) technology to discover innate protease-resistant macrocyclic peptides that specifically bind to and inhibit human MMP7. One identified macrocyclic peptide against D-MMP7, termed D20, was synthesized in its mirror-image form, D'20, consisting of 12 D-amino acids, one cyclic β-amino acid, and a thioether bond. Notably, it potently inhibited MMP7 with an IC50 value of 90 nM, and showed excellent selectivity over other MMPs with similar substrate specificity. Moreover, D'20 inhibited the migration of pancreatic cell line CFPAC-1, but had no effect on the cell proliferation and viability. D'20 exhibited excellent stability in human serum, as well as in simulated gastric and intestinal fluids. This study highlights that MI-RaPID technology can serve as a powerful tool to develop in vivo stable macrocyclic peptides for therapeutic applications.

Mirror‐Image Random Nonstandard Peptides Integrated Discovery (MI‐RaPID) Technology Yields Highly Stable and Selective Macrocyclic Peptide Inhibitors for Matrix Metallopeptidase 7

AbstractMatrix metallopeptidase 7 (MMP7) plays a crucial role in cancer metastasis and progression, making it an attractive target for therapeutic development. However, the development of selective MMP7 inhibitors is challenging due to the conservation of active sites across various matrix metalloproteinases (MMPs). Here, we have developed mirror‐image random nonstandard peptides integrated discovery (MI‐RaPID) technology to discover innate protease‐resistant macrocyclic peptides that specifically bind to and inhibit human MMP7. One identified macrocyclic peptide against D‐MMP7, termed D20, was synthesized in its mirror‐image form, D’20, consisting of 12 D‐amino acids, one cyclic β‐amino acid, and a thioether bond. Notably, it potently inhibited MMP7 with an IC50 value of 90 nM, and showed excellent selectivity over other MMPs with similar substrate specificity. Moreover, D’20 inhibited the migration of pancreatic cell line CFPAC‐1, but had no effect on the cell proliferation and viability. D’20 exhibited excellent stability in human serum, as well as in simulated gastric and intestinal fluids. This study highlights that MI‐RaPID technology can serve as a powerful tool to develop in vivo stable macrocyclic peptides for therapeutic applications.

Unique biogenesis and kinetics of hornwort Rubiscos revealed by synthetic biology systems

Hornworts are the only land plants that employ a pyrenoid to optimize Rubisco’s CO2 fixation. Yet, hornwort Rubisco remains poorly characterized. Here we assemble the hornwort Anthoceros agrestis Rubisco (AaRubisco) using the Arabidopsis thaliana SynBio expression system and observed the formation of stalled intermediates, prompting us to develop a new SynBio system with A. agrestis cognate chaperones. We successfully assembled AaRubisco and Rubisco from three other hornwort species. Unlike A. thaliana Rubisco, AaRubisco assembly is not dependent on RbcX or Raf2. Kinetic characterization reveals that hornwort Rubiscos exhibit a range of catalytic rates (3-10 s-1), but with similar affinity (∼30 μM) and specificity (∼70) for CO2. In other words, hornwort Rubiscos do not comply with the long held canonical catalytic trade-off observed in other land plants, providing experimental support that Rubisco kinetics may be phylogenetically constrained. Unexpectedly, we observed a 50% increase in AaRubisco catalytic rates when RbcX was removed from our SynBio system, without any reduction in specificity. Structural biology, biochemistry and proteomic analysis suggest that subtle differences in Rubisco large subunit interactions, when RbcX is absent during biogenesis, increases the accessibility of active sites and catalytic turnover rate. This study uncovered a previously unknown Rubisco kinetic parameter space and provides a SynBio chassis to expand the survey of other Rubisco kinetics. Our discovery could thus reshape the approaches for engineering Rubisco with superior kinetics.

Using Native and Synthetic Genes to Disrupt Inositol Pyrophosphates and Phosphate Accumulation in Plants.

Inositol pyrophosphates are eukaryotic signaling molecules that have been recently identified as key regulators of plant phosphate sensing and homeostasis. Given the importance of phosphate to current and future agronomic practices, we sought to design plants which could be used to sequester phosphate, as a step in a phytoremediation strategy. To achieve this, we expressed Diadenosine and Diphosphoinositol Polyphosphate Phosphohydrolase (DDP1), a yeast (Saccharomyces cerevisiae) enzyme demonstrated to hydrolyze inositol pyrophosphates, in Arabidopsis thaliana and pennycress (Thlaspi arvense), a spring annual cover crop with emerging importance as a biofuel crop. DDP1 expression in Arabidopsis decreased inositol pyrophosphates, activated Phosphate Starvation Response marker genes, and increased phosphate accumulation. These changes corresponded with alterations in plant growth and sensitivity to exogenously applied phosphate. Pennycress plants expressing DDP1 displayed increases in phosphate accumulation, suggesting that these plants could potentially serve to reclaim phosphate from phosphate-polluted soils. We also identified a native Arabidopsis gene, Nucleoside diphosphate-linked moiety X 13 (NUDIX13), which we show encodes an enzyme homologous to DDP1 with similar substrate specificity. Arabidopsis transgenics overexpressing NUDIX13 had lower inositol pyrophosphate levels and displayed phenotypes similar to DDP1-overexpressing transgenics, while nudix13-1 mutants had increased levels of inositol pyrophosphates. Taken together, our data demonstrates that DDP1 and NUDIX13 can be used in strategies to regulate plant inositol pyrophosphates and could serve as potential targets for engineering plants to reclaim phosphate from polluted environments.

Differentiation of severe from non-severe mitral stenosis with dimensionless index and its prognostic implications in patients with rheumatic mitral stenosis

Abstract Introduction Accurate identification of the severity of rheumatic mitral stenosis (MS) commonly relies on measurement of mitral valve area (MVA) by transthoracic echocardiography (TTE). The dimensionless index (DI) of mitral valve (MV) was recently shown to be useful in identifying severity of degenerative MS. It is uncertain if DI MV is useful in rheumatic MS. Purpose We aimed to validate the DI MV in rheumatic mitral stenosis, identify threshold values of the DI MV for the accurate identification of severe and non-severe rheumatic MS, and study its association with clinically significant outcomes. Methods We studied DI MV in 406 cases of rheumatic MS, with 174 cases in a derivation cohort , 121 cases in a TTE validation cohort, and 111 cases in a transoesophageal echocardiography (TEE) validation cohort. Outcome data were collected in the derivation and TTE validation cohorts. DI MV was calculated by dividing the left ventricular outflow tract pulsed-wave Doppler time-velocity integral (TVI) by the MV continuous-wave Doppler TVI. Results In the derivation cohort, ROC analysis showed that MV DI was significantly associated with MS severity (AUC = 0.838, 95% CI, 0.780-0.897, p<0.001) but no threshold value was able to identify severe MS (MVA ≤ 1.5 cm2) with both sensitivity and specificity greater than 80%. DI MV ≤ 0.34 had the best combination of sensitivity and specificity (78.5% and 75.8% respectively). However, with an approach using two threshold values, namely DI MV ≤ 0.25 to identify severe MS and DI MV ≥ 0.40 to identify non-severe MS, both values showed a high specificity of 93.7%. When tested in the validation cohorts, these values have similar high specificity for identifying severe (93.8%) and non severe MS (91.4%). DI MV was univariately significant (HR = 0.075, 95% CI 0.0215-0.378, p=0.002) in Cox regression analysis for a composite outcome of death and MV intervention. Multivariate analysis incorporating age, sex, DI MV, pulmonary artery systolic pressure (PASP) and left ventricular ejection fraction (LVEF) showed that age, DI MV and PASP were independently associated with the composite outcome. Conclusion While not a replacement for MVA in the assessment of MS severity, the DI MV can rule-in or rule-out severe MS with a high specificity and is useful as a complementary tool in the integrative assessment of MS severity. DI MV is independently associated with composite outcomes of death and MV intervention.Receiver operating characteristic curveSensitivity and Specificity of DI MV

Monitoring focused ultrasound ablation surgery (FUAS) using echo amplitudes of the therapeutic focused transducer

ObjectiveB-mode sonography is commonly used to monitor focused ultrasound ablation surgery (FUAS), but has limitations in sensitivity. More accurate and reliable prediction of coagulation is required. MethodsThe focused ultrasound (FUS) transducer was adapted for echo reception. Numerical simulations compared the normalized echo amplitudes from the FUS transducer and imaging probe at varying tissue depths and frequencies with a 3 mm necrosis at focus. An ex vivo experiment then evaluated echo changes from the FUS transducer and ultrasound imaging probe under different settings. Finally, coagulation prediction using FUS echo data was compared to sonography in a clinical ex vivo context. ResultsThe echo amplitudes from the FUS transducer exhibit a less pronounced decline with increasing tissue penetration depth compared to the ultrasound imaging probe. In ex vivo bovine liver experiments at depths of 2 cm and 4 cm, the FUS transducer detected normalized echo amplitudes that were significantly larger (i.e., 2∼3 folds) than those received by the ultrasound imaging probe. Moreover, multi-layered ex vivo tissue experiments that replicate clinical conditions revealed that coagulation prediction utilizing the FUS transducer's echo amplitudes achieved superior accuracy (91.2% vs. 60.3 %), sensitivity (92.1% vs. 54.5 %), and negative prediction (78.9% vs. 30.6 %), but similar specificity (88.2% vs. 84.6 %) and positive prediction (95.9% vs. 93.8 %) in comparison to sonography. ConclusionThe echo amplitude of the FUS transducer serves as a sensitive and dependable metric for monitoring the FUAS outcomes. Its utilization may augment the procedure's safety and efficacy.

18F]FDG PET/CT versus [18F]FDG PET/MRI in the diagnosis of lymph node metastasis in nasopharyngeal carcinoma: a systematic review and meta-analysis.

This meta-analysis aimed to evaluate the comparative diagnostic accuracy of [18F]FDG PET/CT versus [18F]FDG PET/MRI in identifying lymph node metastases in individuals with nasopharyngeal carcinoma. A comprehensive search was executed across PubMed, Embase, and Web of Science through September 2023 to identify studies evaluating the diagnostic precision of [18F]FDG PET/CT and [18F]FDG PET/MRI in detecting lymph node metastasis in nasopharyngeal carcinoma. Sensitivity and specificity were assessed through the DerSimonian-Laird method, incorporating the Freeman-Tukey transformation. The meta-analysis encompassed nine articles, involving a total of 916 patients. The overall sensitivity and specificity of [18F]FDG PET were 0.95 (95%CI: 0.88-1.00) and 0.95 (95%CI: 0.84-1.00). The overall sensitivity of [18F]FDG PET/CT was 0.94 (95%CI, 0.85-0.99), whereas [18F]FDG PET/MRI achieved a sensitivity of 1.00 (95%CI, 0.94-1.00). The findings reveal that [18F]FDG PET/CT demonstrates comparable sensitivity to [18F]FDG PET/MRI (p = 0.20). The overall specificity of [18F]FDG PET/CT was 0.94 (95%CI, 0.82-1.00), whereas [18F]FDG PET/MRI exhibited a specificity of 0.98 (95%CI, 0.93-1.00). Additionally, the results suggest that [18F]FDG PET/CT offers similar specificity to [18F]FDG PET/MRI (p = 0.11). [18F]FDG PET demonstrates high sensitivity and specificity in identifying lymph node metastasis in nasopharyngeal carcinoma. Furthermore, [18F]FDG PET/CT exhibits comparable sensitivity and specificity to [18F]FDG PET/MRI. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=496006, PROSPERO (CRD42024496006).

Evaluation and comparison of performances of six commercial NSP ELISA assays for foot and mouth disease virus in Thailand

ELISA kits that detect antibodies to the non-structural protein (NSP) of the foot-and-mouth disease virus (FMDV), commonly referred to as NSP-ELISA, can distinguish between vaccinated and naturally infected animals. They can play an essential role in demonstrating ‘proof-of-freedom’ during the control of FMD. Although various NSP-ELISA kits are available in Thailand, information regarding their performance is lacking. To select the most appropriate NSP-ELISA kit for our specific purpose, we must compare their performance using carefully characterized sera. This will ensure that we maximize the benefits of our testing. In this study, six NSP-ELISA kits sold in Thailand―Biovet, ID Screen, VDPro, IDEXX, PrioCHECK, and KUcheck-F―were evaluated and compared. A total of 800 serum samples were examined, including samples from 357 cattle and 29 buffaloes in outbreak areas, as well as 14 swine serum samples from the Vaccine Quality Control Unit of the Bureau of Veterinary Biologics, Ministry of Agriculture and Cooperation, Thailand. Four hundred samples were confirmed to originate from animals infected with FMDV through ELISA typing (n = 11, tested as representative samples in each farm) and/or RT-PCR (n = 400, all samples), serving as positive control sera. Additionally, 400 negative control sera were obtained from Japan (97 cattle and 300 pigs) and Australia (3 goats), certified by the World Organisation for Animal Health as ‘free of FMD’. The sensitivity and specificity of the six tests were determined based on the results obtained from two-by-two tables. Cohen’s kappa statistics were calculated for the six tests to assess their concordance, and the diagnostic accuracy of the assays was also determined. For all six NSP-ELISA kits, the sensitivity ranged from 97.75 to 99.50%, and the specificity ranged from 97.25 to 100%. Cohen’s kappa statistics ranged from 0.96 to 1.00, and diagnostic accuracy ranged from 98.13 to 99.75%. The study results indicated that the test kits have statistically similar sensitivity, specificity, concordance, and diagnostic accuracy, suggesting they can be used interchangeably. However, ID Screen demonstrated the highest sensitivity and specificity among all kits tested. Therefore, if a single kit were to be selected from the six evaluated, ID Screen would be the most appropriate choice. These findings can aid in selecting the most suitable test kit. Therefore, it is recommended to consider purchasing a diverse range of effective test kits. Furthermore, these findings can provide guidance for expanding the use of test kits, particularly with the growing availability of NSP-ELISA kits in the market.

Bidirectional regulation of motor circuits using magnetogenetic gene therapy.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Clinical associations of complement-activating collectins, collectin-10, collectin-11 and mannose-binding lectin in preterm neonates.

Premature and low-birthweight infants are at especially high risk of perinatal complications, including impaired thermoregulation, infections and respiratory distress. Such adverse effects and the need for invasive procedures are associated with high mortality among preterms. This study focused on the influence of the innate immune system and tested the levels of collectins, collectin-10 (CL-10), collectin-11 (CL-11) and mannose-binding lectin (MBL) in preterm neonates. Cord blood was collected from 535 preterms (born at gestational age ≤37 weeks). COLEC10 and COLEC11 polymorphisms were analyzed by real-time PCR and those of MBL2 by PCR/PCR-RFLP. The concentrations of collectins in sera from cord blood were determined with ELISA. Low concentrations of CL-10 in cord sera (<462 ng/ml corresponding to the 10th percentile) were significantly associated with births at GA ≤32 weeks. Median levels of both CL-10 and CL-11 were significantly lower in preterms with very low birthweight (<1500 g), low Apgar 1' score and those who needed prolonged hospitalisation. Lower median CL-10 was also observed in fetal growth restriction cases. An important finding was the decreased concentrations of CL-10, CL-11 and MBL in respiratory distress syndrome (RDS). For CL-10 and CL-11, that relationship was confined to infants born at GA ≥33 weeks and/or with body mass at birth ≥1500 g. Only CL-10 was found to influence susceptibility to early-onset infections. COLEC11 heterozygosity for the activity-decreasing polymorphism (rs7567833, +39618 A>G, His219Arg) was more common in preterm premature rupture of membranes (pPROM) cases, compared with corresponding reference groups. Furthermore, C/T or T/T genotypes at COLEC11 at rs3820897 (-9570 C>T) as well as MBL deficiency-associated MBL2 gene variants were more common in preterms diagnosed with RDS than among unaffected newborns. The complement-activating collectins investigated here could be important for maintaining homeostasis in preterm neonates. Despite similar structure and specificity, MBL, CL-10 and CL-11 manifest a different spectrum of clinical associations.

Evaluation of different standard and modified two-tier testing strategies for the laboratory diagnosis of lyme borreliosis in a European setting.

Diagnosis of Lyme borreliosis (LB) relies on clinical symptoms and detection of Borrelia-specific antibodies. Guidelines recommend a two-tier testing (TTT) strategy for disseminated LB: serological screening with a sensitive enzyme immunoassay (EIA) and confirmation with a specific immunoblot. Searching for the most sensitive and specific approach, this retrospective study evaluated standard (STTT) and modified (MTTT) strategies using a well-defined study population. Cases included patients with active Lyme neuroborreliosis (LNB; n = 29) or Lyme arthritis (LA; n = 17). Controls comprised patients treated for LNB (n = 36) or LA (n = 8), healthy individuals who were either untreated (n = 75) or treated for LB (n = 15) in the past, and patients with potentially cross-reactive diseases (n = 16). Sera were subjected to three EIAs and two immunoblots. Reactive screening results were confirmed by immunoblot (STTT) or EIA (MTTT). Solitary IgM results in the screening assay and effects of antibiotic treatment on isotype-specific seropositivity rates were also assessed. Sensitivities of STTT strategies ranged from 90%-97% for LNB and were 100% for LA. MTTT strategies were 100% sensitive. Specificities ranged from 89%-95% for STTT and from 88%-93% for MTTT strategies. Differences between STTT and MTTT strategies were not statistically significant. Solitary IgM reactivity was common among controls. Antibiotic treatment significantly reduced IgM/IgG positivity for LNB patients; for LA patients, a decline was only observed for IgM. In conclusion, MTTT strategies showed a slightly higher sensitivity and similar specificity compared to STTT strategies. Since EIAs are more time- and cost-efficient, MTTT strategies seem more favorable for clinical use. IgG testing enhances specificity with minimal sensitivity loss.

Validation of a Dermatoscopy-Based Algorithm for the Diagnosis of Acral Melanoma

Introduction: Diagnosis of acral melanocytic lesions can be challenging. The BRAAFF checklist was introduced as a tool to help differentiate between acral nevi and melanoma but has not been validated. Methods: We asked raters with varying expertise in dermatoscopy to diagnose dermatoscopic images of 533 acral nevi and 144 melanomas via an online platform with and without use of the BRAAFF checklist. From the ratings, we calculated sensitivity, specificity, and interrater agreement. Additionally, a new simplified version of the checklist was also tested. Results: We collected 6,880 ratings from 175 readers. The BRAAFF checklist achieved a sensitivity of 92.5% and a specificity of 65.0%, which was similar to diagnosis from pattern recognition (sensitivity 90.0%, specificity: 72.1%). Interrater agreement for the BRAAFF criteria ranged from fair to moderate, with lowest agreement for parallel ridge and fibrillar pattern (alpha = 0.31) and highest for asymmetry of colors and structures (alpha = 0.46). Agreement and diagnostic accuracy were higher for more experienced readers. A simplified version with only two criteria achieved similar sensitivity (95.0%) and lower specificity (60.0%) as the original BRAAFF checklist. Conclusion: The BRAAFF checklist is a useful tool for the diagnosis of melanocytic acral lesions with acceptable sensitivity and reasonable specificity but is not superior to pattern recognition. A simplified version of the checklist could be easier to use with equal sensitivity while exhibiting a modest reduction in specificity.

Comparative Diagnostic Performance of Amyloid-β Positron Emission Tomography and Magnetic Resonance Imaging in Alzheimer's Disease: A Head-to-Head Meta-Analysis.

This meta-analysis aimed to evaluate the comparative diagnostic performance of amyloid-β positron emission tomography (Aβ PET) and magnetic resonance imaging (MRI) in diagnosing Alzheimer's disease (AD). An extensive search was conducted in the PubMed and Embase databases to identify available publications up to December 2023. Head-to-head comparative studies were included if they evaluated the diagnostic performance of Aβ PET and MRI in diagnosing Alzheimer's disease. Sensitivity and specificity were assessed using the DerSimonian and Laird method, followed by transformation via the Freeman-Tukey double inverse sine transformation. Six articles involving 560 patients were included in the meta-analysis. When distinguishing AD from mild cognitive impairment (MCI), both methods showed comparable sensitivity (Aβ PET: 0.71, MRI: 0.62) and specificity (Aβ PET: 0.68, MRI: 0.69), with no statistically significant differences observed (p = 0.34 and 0.99). When identifying AD from normal cognitive control (NC), both Aβ PET and MRI showed similar results, with comparable sensitivity (Aβ PET: 0.93, MRI: 0.85) and specificity (Aβ PET: 0.95, MRI: 0.82), without significant differences (p = 0.38 and 0.19). Similarly, in detecting MCI from NC, both Aβ PET and MRI demonstrated similar sensitivity (Aβ PET: 0.69, MRI: 0.64) and specificity (Aβ PET: 0.75, MRI: 0.76) without significant differences (p = 0.40 and 0.94). However, 18F-FMM seems to have a higher specificity compared to MRI when distinguishing AD from MCI (P = 0.03) and AD from NC (p = 0.04). Our meta-analysis indicates that Aβ PET demonstrates similar sensitivity and specificity to MRI in diagnosing Alzheimer's disease. However, the limited number of studies may impact the evidence of the current study; further larger sample prospective research is required to confirm these findings.

The sensitivity and specificity of fine needle aspiration cytology in detecting thyroid malignancy according to Bethesda system at a teaching hospital in Saudi Arabia

ABSTRACT Background: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) aims to standardize the terminology and morphologic criteria associated with thyroid fine-needle aspiration cytology (FNAC) results while also providing corresponding risk assessments for malignancy. contributing to more consistent and standardized reporting of thyroid nodules and aiding clinicians in making informed decisions. Since then, it has been undergoing revisions and updates to further improve its utility and accuracy. Materials and Methods: This is a retrospective study conducted at a tertiary care center. All patients with a history of thyroid gland swelling who had previously undergone FNA were included. The procedure included cytopathologists performing FNAC for all cases of midline neck swelling. Demographic and histopathology data were correlated with the cytological diagnosis. Results: We included 288 cases. Of those, 234 (81.3%) were female and 54 (18.8%) were male. The presentation age range was 18–91 years. The most reported category was benign, which constituted 30.9% of the cases followed by malignancy (27.1%). As for thyroid lesions, papillary carcinoma was the most prevalent (43.6%). The correlation on cyto-histopathology was presented in every diagnostic category, showing high heterogeneity in diagnostic specificity and sensitivity. The overall diagnostic specificity and sensitivity were 56.05% (95% confidence interval [CI]: 47.92–63.95%) and 80.92% (95% CI: 73.13–87.25%), respectively. Positive and negative predictive values were 60.57% and 77.88%, respectively. Conclusion: Our data suggests that the TBSRTC system promotes similar sensitivity and specificity to those reported elsewhere. It standardizes reporting and improves communication between cytopathologists and clinicians.

Risk-prediction models in postmenopausal patients with symptoms of suspected ovarian cancer in the UK (ROCkeTS): a multicentre, prospective diagnostic accuracy study

Multiple risk-prediction models are used in clinical practice to triage patients as being at low risk or high risk of ovarian cancer. In the ROCkeTS study, we aimed to identify the best diagnostic test for ovarian cancer in symptomatic patients, through head-to-head comparisons of risk-prediction models, in a real-world setting. Here, we report the results for the postmenopausal cohort. In this multicentre, prospective diagnostic accuracy study, we recruited newly presenting female patients aged 16-90 years with non-specific symptoms and raised CA125 or abnormal ultrasound results (or both) who had been referred via rapid access, elective clinics, or emergency presentations from 23 hospitals in the UK. Patients with normal CA125 and simple ovarian cysts of smaller than 5 cm in diameter, active non-ovarian malignancy, or previous ovarian malignancy, or those who were pregnant or declined a transvaginal scan, were ineligible. In this analysis, only postmenopausal participants were included. Participants completed a symptom questionnaire, gave a blood sample, and had transabdominal and transvaginal ultrasounds performed by International Ovarian Tumour Analysis consortium (IOTA)-certified sonographers. Index tests were Risk of Malignancy 1 (RMI1) at a threshold of 200, Risk of Malignancy Algorithm (ROMA) at multiple thresholds, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) at thresholds of 3% and 10%, IOTA SRRisk model at thresholds of 3% and 10%, IOTA Simple Rules (malignant vs benign, or inconclusive), and CA125 at 35 IU/mL. In a post-hoc analysis, the Ovarian Adnexal and Reporting Data System (ORADS) at 10% was derived from IOTA ultrasound variables using established methods since ORADS was described after completion of recruitment. Index tests were conducted by study staff masked to the results of the reference standard. The comparator was RMI1 at the 250 threshold (the current UK National Health Service standard of care). The reference standard was surgical or biopsy tissue histology or cytology within 3 months, or a self-reported diagnosis of ovarian cancer at 12 month follow-up. The primary outcome was diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C-index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN17160843). Between July 13, 2015, and Nov 30, 2018, 1242 postmenopausal patients were recruited, of whom 215 (17%) had primary ovarian cancer. 166 participants had missing, inconclusive, or other reference standard results; therefore, data from a maximum of 1076 participants were used to assess the index tests for the primary outcome. Compared with RMI1 at 250 (sensitivity 82·9% [95% CI 76·7 to 88·0], specificity 87·4% [84·9 to 89·6]), IOTA ADNEX at 10% was more sensitive (difference of -13·9% [-20·2 to -7·6], p<0·0001) but less specific (difference of 28·5% [24·7 to 32·3], p<0·0001). ROMA at 29·9 had similar sensitivity (difference of -3·6% [-9·1 to 1·9], p=0·24) but lower specificity (difference of 5·2% [2·5 to 8·0], p=0·0001). RMI1 at 200 had similar sensitivity (difference of -2·1% [-4·7 to 0·5], p=0·13) but lower specificity (difference of 3·0% [1·7 to 4·3], p<0·0001). IOTA SRRisk model at 10% had similar sensitivity (difference of -4·3% [-11·0 to -2·3], p=0·23) but lower specificity (difference of 16·2% [12·6 to 19·8], p<0·0001). IOTA Simple Rules had similar sensitivity (difference of -1·6% [-9·3 to 6·2], p=0·82) and specificity (difference of -2·2% [-5·1 to 0·6], p=0·14). CA125 at 35 IU/mL had similar sensitivity (difference of -2·1% [-6·6 to 2·3], p=0·42) but higher specificity (difference of 6·7% [4·3 to 9·1], p<0·0001). In a post-hoc analysis, when compared with RMI1 at 250, ORADS achieved similar sensitivity (difference of -2·1%, 95% CI -8·6 to 4·3, p=0·60) and lower specificity (difference of 10·2%, 95% CI 6·8 to 13·6, p<0·0001). In view of its higher sensitivity than RMI1 at 250, despite some loss in specificity, we recommend that IOTA ADNEX at 10% should be considered as the new standard-of-care diagnostic in ovarian cancer for postmenopausal patients. UK National Institute of Heath Research.

Real-world diagnostic accuracy of lipoarabinomannan in three non-sputum biospecimens for pulmonary tuberculosis disease

Development of a non-sputum test using readily-obtainable biospecimens remains a global priority for tuberculosis (TB) control. We quantified lipoarabinomannan (LAM) concentrations, a pathogen biomarker for Mycobacterium tuberculosis, in urine, plasma and serum for real-world diagnostic accuracy of pulmonary TB among people living with and without HIV. We conducted a prospective diagnostic study among adults with TB symptoms in South Africa. We measured LAM concentrations in time-matched urine, plasma and serum with an electrochemiluminescence immunoassay using two capture antibodies (FIND 28 and S4-20). From the completed cohort, we randomly selected 210 participants (2 cases: 1 control) based on sensitivity estimates, and we compared diagnostic accuracy of LAM measurements against the microbiological reference standard. Urine and blood specimens from 210 of 684 adults enrolled were tested for LAM. Among 138TB-positive adults (41% female), median urine LAM was 137pg/mL and 52pg/mL by FIND 28 and S4-20, respectively. Average LAM concentrations were highest in HIV-positive participants with CD4+ T cells <200cells/mm3. Urine LAM by S4-20 achieved diagnostic sensitivity of 62% (95% CI: 53%-70%) and specificity of 99% (95% CI: 96%-100%). Plasma and serum LAM by FIND 28 showed similar sensitivity (70%, 95% CI: 62%-78%) and comparable specificities (90%, 95% CI: 82%-97%; 94%, 95% CI: 88%-99%). Diagnostic sensitivity of urine LAM by S4-20 was higher among participants without HIV (41%, 95% CI: 24%-61%) compared to HIV-positive participants with CD4 ≥200cells/mm3 (20%, 95% CI: 8%-39%). Detection of LAM was achievable in non-sputum specimens for pulmonary TB, but additional analyte concentration or signal amplification may be required to achieve diagnostic accuracy targets. Bill and Melinda Gates Foundation.

Comparing the diagnostic efficacy of [18F]FDG PET/CT and MRI in the initial diagnosis of ovarian cancer: a meta-analysis.

This meta-analysis was conducted to assess the relative diagnostic effectiveness of [18F]FDG PET/CT and MRI in the initial detection of ovarian cancer. A thorough literature search was conducted using PubMed, Embase, and Web of Science databases to locate relevant studies published up to April 2024. The selected studies were those that evaluated diagnostic performance of [18F]FDG PET/CT and MRI for the initial detection of ovarian cancer. Sensitivity and specificity metrics were analyzed employing the DerSimonian and Laird random-effects model, with further transformation utilizing the Freeman-Tukey double arcsine method. The quality of included studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The meta-analysis included 23 articles encompassing a total of 1973 patients. The sensitivity of [18F]FDG PET/CT was found to be higher than that of MRI (0.94 vs. 0.87, P = 0.02). In terms of specificity, [18F]FDG PET/CT and MRI demonstrated similar values (0.87 vs. 0.86, P = 0.90). An assessment of publication bias using the funnel plot asymmetry test revealed no significant bias for any outcomes (Egger's test: all P > 0.05). Our meta-analysis reveals that [18F]FDG PET/CT exhibits higher sensitivity while maintaining similar specificity compared to MRI for the initial detection of ovarian cancer. However, the substantial heterogeneity observed across studies may influence these findings. Consequently, larger-scale prospective studies are necessary to validate these results.

The association between trimethylamine N-oxide levels and coronary microvascular dysfunction and prognosis in patients with ST-elevation myocardial infarction

Background and aimsCoronary microvascular dysfunction (CMD) is common after ST-elevation myocardial infarction (STEMI), leading to adverse clinical outcomes. However, its diagnosis remains difficult, and mechanisms elusive. This study explores the role of Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, as a potential biomarker for diagnosing CMD in STEMI patients. MethodsThis prospective, observational study enrolled 210 STEMI patients with multivessel coronary artery disease who underwent primary percutaneous coronary intervention (PCI). TMAO levels were measured at baseline, 3 months, and 12 months post-PCI, whilst coronary physiology was assessed at 3 months. The primary endpoint was the incidence of CMD at 3 months, with the secondary endpoint being major adverse cardiovascular and cerebrovascular events (MACCE) at 12 months. An additional 59 consecutive patients were enrolled for validation. ResultsTMAO levels varied from baseline to 3 months, then stabilised. The areas under the ROC curve for baseline TMAO and TMAO at 3-month were 0.55 (95 % CI 0.46–0.64; p = 0.426), and 0.80 (95 % CI 0.73–0.87; p < 0.001), respectively. The optimal cut-off for TMAO at 3-month to diagnose CMD was 3.91, with similar sensitivity and specificity in the derivation and validation cohort. The incidence of MACCE was higher in patients with TMAO≥3.91 (41.4 % vs 10.7 %; p < 0.001). The addition of 3-month TMAO improved the diagnostic performance of traditional risk factors. ConclusionTMAO is a robust biomarker for CMD and is significantly associated with the incidence of MACCE. TMAO has the potential in guiding clinical decision-making and suggests an interplay between gut microbiota and CMD.