Deep learning to detect left ventricular structural abnormalities in chest X-rays.

BACKGROUND AND AIMS: Early identification of cardiac structural abnormalities indicative of heart failure is crucial to improving patient outcomes. Chest X-rays (CXRs) are routinely conducted on a broad population of patients, presenting an opportunity to build scalable screening tools for structural abnormalities indicative of Stage B or worse heart failure with deep learning methods. In this study, a model was developed to identify severe left ventricular hypertrophy (SLVH) and dilated left ventricle (DLV) using CXRs. METHODS: A total of 71 589 unique CXRs from 24 689 different patients completed within 1 year of echocardiograms were identified. Labels for SLVH, DLV, and a composite label indicating the presence of either were extracted from echocardiograms. A deep learning model was developed and evaluated using area under the receiver operating characteristic curve (AUROC). Performance was additionally validated on 8003 CXRs from an external site and compared against visual assessment by 15 board-certified radiologists. RESULTS: The model yielded an AUROC of 0.79 (0.76-0.81) for SLVH, 0.80 (0.77-0.84) for DLV, and 0.80 (0.78-0.83) for the composite label, with similar performance on an external data set. The model outperformed all 15 individual radiologists for predicting the composite label and achieved a sensitivity of 71% vs. 66% against the consensus vote across all radiologists at a fixed specificity of 73%. CONCLUSIONS: Deep learning analysis of CXRs can accurately detect the presence of certain structural abnormalities and may be useful in early identification of patients with LV hypertrophy and dilation. As a resource to promote further innovation, 71 589 CXRs with adjoining echocardiographic labels have been made publicly available.

Vertical directional coupling based grating emission engineering for optical phased arrays.

In this Letter, a novel, to the best of our knowledge, vertical directional coupling waveguide grating (VDCWG) architecture is proposed to increase the length of waveguide grating antennas for large aperture on-chip optical phased arrays (OPAs). In this new architecture, the grating emission strength is engineered by the vertical directional coupler, which provides additional degrees of design freedom. Theoretical analysis and numerical simulation show that the VDCWG can adjust the grating strength in the range of more than two orders of magnitude, corresponding to an effective grating length more than a centimeter. For proof-of-concept, a VDCWG antenna with a length of 1.5 mm is experimentally demonstrated. The grating strength is measured to be 0.17 mm-1, and the far-field divergence angle is 0.061°. A 16-channel OPA is also developed based on the proposed VDCWG, which proves the potential of the new architecture for large aperture OPAs.

Development of introgression lines and mapping of qGW2, a novel QTL that confers grain width, in rice (Oryza sativa L.).

Rice grain size is a key determinant of both grain yield and quality. Identification of favorable alleles for use in rice breeding may help to meet the demand for increased yield. In this study, we developed a set of 210 introgression lines (ILs) by using indica variety Huanghuazhan as the donor parent and erect-panicle japonica rice variety Wuyujing3R as the recurrent parent. A total of 133 ILs were selected for high-throughput sequencing. Using specific-locus amplified fragment (SLAF) sequencing technology, 10,103 high-quality SLAF labels evenly distributed on 12 chromosomes were obtained and selected for subsequent analysis. Using a high-density map, quantitative trait locus (QTL) mapping of grain size-related traits was performed, and a total of 38 QTLs were obtained in two environments. Furthermore, qGW2, a novel QTL that controls grain width on chromosome 2, was validated and delimited to a region of 309 kb via substitution mapping. These findings provide new genetic material and a basis for future fine mapping and cloning of favorable QTLs. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01453-0.

Circularly Polarized Luminescence Induced by Hydrogen-Bonding Networks in a One-Dimensional Hybrid Manganese(II) Chloride.

Chiral hybrid metal halides hold great potential as circularly polarized luminescence light sources. Herein, we have obtained two enantiomeric pairs of one-dimensional hybrid chiral manganese(II) chloride single crystals, R/S-(3-methyl piperidine)MnCl3 (R/S-1) and R/S-(3-hydroxy piperidine)MnCl3 (R/S-2), crystallizing in the non-centrosymmetric space group P212121. In comparison to R/S-1, R/S-2 single crystals not only show red emission with near-unity photoluminescence quantum yield (PLQY) and high resistance to thermal quenching but also exhibit circularly polarized luminescence with an asymmetry factor (glum) of 2.5×10-3, which can be attributed to the enhanced crystal rigidity resulting from the hydrogen bonding networks between R/S-(3-hydroxy piperidine) cations and [MnCl6]4- chains. The circularly polarized luminescence activities originate from the asymmetric [MnCl6]4- luminophores induced by N-H⋅⋅⋅Cl hydrogen bonding with R/S-(3-hydroxy piperidine). Moreover, these samples demonstrate great application potential in circularly polarized light-emitting diodes and X-ray scintillators. This work shows a highly efficient photoluminescent Mn-based halide and offers a strategy for designing multifunctional chiral metal halides.

Single-cell transcriptomic survey of cell diversity and functional changes in yak hearts at different altitude.

The yak (Bos grunniens) is a species adapted to the hypoxic environment in the plateau area. The heart is a hypoxia-sensitive organ involved in this adaptation. Herein, we used single-cell RNA-seq technology and clustering to determine the presence of 11 cell populations in the yak heart. We analyzed gene expression differences and expression patterns in each cell subpopulation at different altitudes. The cells related to altitude changes are mainly smooth muscle cells and vascular endothelial cells. Of the four transcription factors (TFs, MEF2B, FOXP4, ARID5A, and HES4) found in smooth muscle cells, only MEF2B was specifically expressed in vascular smooth muscle cells. Three key TFs (HNF1B, DMRTA1, and ARNTL2) were also found in the cardiomyocyte module. Compared with data extracted from low-altitude yak, we observed that the high altitude yak has enhanced contraction and relaxation of vascular smooth muscle cells and an increased metabolic level of cardiomyocytes. These may be strategies for the yak to adapt to high-altitude hypoxia environments.

PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1.

BACKGROUND: Breast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain. METHODS: We identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP. RESULTS: PAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3'UTR region, respectively. CONCLUSION: In summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy.

Utilization of PAX1 methylation test for cervical cancer screening of non-HPV16/18 high-risk HPV infection in women.

Aim: To evaluate the clinical performance of PAX1 methylation (PAX1m) and cytology for patients with non-HPV16/18 high-risk HPV (hrHPV) infection. Methods: Cervical exfoliated cells from 387 outpatients with non-HPV16/18 hrHPV - positive were collected for cytology and PAX1m assays. Results: The PAX1m level increased with the severity of cytology and histopathology. For cervical intraepithelial neoplasia (CIN)CIN2+/CIN3+, the areas under the curve were both 0.87. The specificity and positive predictive value (PPV) of PAX1m were greater than abnormal cytology (CIN2+ specificity: 75.5 vs 24.8%; PPV: 38.8 vs 18.7%; CIN3+ specificity: 69.3 vs 22.7%; PPV: 14.0 vs 6.7%). Conclusion: PAX1m increased specificity and PPV for CIN2+/CIN3+ compared with cytology for women with non-HPV16/18 hrHPV (+).

Multicenter Study of the Utility of Convolutional Neural Network and Transformer Models for the Detection and Segmentation of Meningiomas.

PURPOSE: This study aimed to investigate the effectiveness and practicality of using models like convolutional neural network and transformer in detecting and precise segmenting meningioma from magnetic resonance images. METHODS: The retrospective study on T1-weighted and contrast-enhanced images of 523 meningioma patients from 3 centers between 2010 and 2020. A total of 373 cases split 8:2 for training and validation. Three independent test sets were built based on the remaining 150 cases. Six convolutional neural network detection models trained via transfer learning were evaluated using 4 metrics and receiver operating characteristic analysis. Detected images were used for segmentation. Three segmentation models were trained for meningioma segmentation and were evaluated via 4 metrics. In 3 test sets, intraclass consistency values were used to evaluate the consistency of detection and segmentation models with manually annotated results from 3 different levels of radiologists. RESULTS: The average accuracies of the detection model in the 3 test sets were 97.3%, 93.5%, and 96.0%, respectively. The model of segmentation showed mean Dice similarity coefficient values of 0.884, 0.834, and 0.892, respectively. Intraclass consistency values showed that the results of detection and segmentation models were highly consistent with those of intermediate and senior radiologists and lowly consistent with those of junior radiologists. CONCLUSIONS: The proposed deep learning system exhibits advanced performance comparable with intermediate and senior radiologists in meningioma detection and segmentation. This system could potentially significantly improve the efficiency of the detection and segmentation of meningiomas.

MEIS1 Is a Common Transcription Repressor of the miR-23a and NORHA Axis in Granulosa Cells.

MicroRNA-23a (miR-23a) is an endogenous small activating RNA (saRNA) involved in ovarian granulosa cell (GC) apoptosis and sow fertility by activating lncRNA NORHA transcription. Here, we reported that both miR-23a and NORHA were repressed by a common transcription factor MEIS1, which forms a small network regulating sow GC apoptosis. We characterized the pig miR-23a core promoter, and the putative binding sites of 26 common transcription factors were detected in the core promoters of both miR-23a and NORHA. Of them, transcription factor MEIS1 expression was the highest in the ovary, and widely distributed in various ovarian cells, including GCs. Functionally, MEIS1 is involved in follicular atresia by inhibiting GC apoptosis. Luciferase reporter and ChIP assays showed that transcription factor MEIS1 represses the transcription activity of miR-23a and NORHA through direct binding to their core promoters. Furthermore, MEIS1 represses miR-23a and NORHA expression in GCs. Additionally, MEIS1 inhibits the expression of FoxO1, a downstream of the miR-23a/NORHA axis, and GC apoptosis by repressing the miR-23a/NORHA axis. Overall, our findings point to MEIS1 as a common transcription repressor of miR-23a and NORHA, and develop the miR-23a/NORHA axis into a small regulatory network regulating GC apoptosis and female fertility.

Rapid Color-Switching of MnO2 Hollow-Nanosphere Films in Dynamic Water Vapor for Reversible Optical Encryption.

Drop-casting manganese oxide (MnO2 ) hollow nanospheres synthesized via a simple surface-initiated redox route produces thin films exhibiting angle-independent structural colors. The colors can rapidly change in response to high-humidity dynamic water vapor (relative humidity > 90%) with excellent reversibility. When the film is triggered by dynamic water vapor with a relative humidity of ≈100%, the color changes with an optimal wavelength redshift of ≈60 nm at ≈600 ms while there is no shift under static water vapor. The unique selective response originates from the nanoscale porosity formed in the shells by randomly stacked MnO2 nanosheets, which enhances the capillary condensation of dynamic water vapor and promotes the change of their effective refractive index for rapid color switching. The repeated color-switching tests over 100 times confirm the durability and reversibility of the MnO2 film. The potential of these films for applications in anti-counterfeiting and information encryption is further demonstrated by reversible encoding and decoding initiated exclusively by exposure to human breath.

Transition in the growth mode of plasmonic bubbles in binary liquids.

Multi-component fluids with phase transitions show a plethora of fascinating phenomena with rich physics. Here we report on a transition in the growth mode of plasmonic bubbles in binary liquids. By employing high-speed imaging we reveal that the transition is from slow evaporative to fast convective growth and accompanied by a sudden increase in radius. The transition occurs as the three-phase contact line reaches the spinodal temperature of the more volatile component leading to massive, selective evaporation. This creates a strong solutal Marangoni flow along the bubble which marks the beginning of convective growth. We support this interpretation by simulations. After the transition the bubble starts to oscillate in position and in shape. Though different in magnitude the frequencies of both oscillations follow the same power law , which is characteristic of bubble shape oscillations, with the surface tension σ as the restoring force and the bubble's added mass as inertia. The transitions and the oscillations both induce a strong motion in the surrounding liquid, opening doors for various applications where local mixing is beneficial.

[A large-scale retrospective analysis of copy number variations in single center using ACMG-ClinGen latest guidelines].

OBJECTIVE: Through a retrospective large sample analysis of copy number variants in single center, we explored the technical standards for the interpretation and reporting of constitutional copy-number variants (CNVs) jointly proposed by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) in 2019, analyzing its impact on CNVs ratings and the improvement in the consistency of the classification of CNVs in clinical laboratories. METHODS: 236 CNVs that assessed as pathogenic, uncertain significant (including likely pathogenic, uncertain and likely benign) by the 2011 ACMG guidelines between August 2018 and December 2019 in our center were re-analyzed. Four working group members of the center reclassified and evaluated 235 CNVs according to 2019 ACMG guidelines. RESULTS: The consistency of clinical significance classification of CNVs was 91% and the α test coefficient was 0.98 among four working group members. Compared with the 2011 and 2019 ACMG technical standards for the CNVs classification, evaluation of pathogenicity and uncertain significant is basically consistent. 90% (45/50) of likely pathogenic and likely benign CNVs were Re-evaluated as variants of uncertain significance, and the difference is significant. CONCLUSION: The new version ACMG/ClinGen guidelines for the evaluation of CNVs developed semi-quantitative point-based scoring system and help to improve the consistency in clinical classifications. It can also make the interpretation of CNVs more standardized and transparent.

Collective Entrainment and Confinement Amplify Transport by Schooling Microswimmers.

Microswimmers can serve as cargo carriers that move deep inside complex flow networks. When a school collectively entrains the surrounding fluid, their transport capacity can be enhanced. This effect is quantified with good agreement between experiments with self-propelled droplets and a confined Brinkman squirmer model. The volume of liquid entrained can be much larger than the droplet itself, amplifying the effective cargo capacity over an order of magnitude, even for dilute schools. Hence, biological and engineered swimmers can efficiently transport materials into confined environments.

Propelling microdroplets generated and sustained by liquid-liquid phase separation in confined spaces.

Flow transport in confined spaces is ubiquitous in technological processes, ranging from separation and purification of pharmaceutical ingredients by microporous membranes and drug delivery in biomedical treatment to chemical and biomass conversion in catalyst-packed reactors and carbon dioxide sequestration. In this work, we suggest a distinct pathway for enhanced liquid transport in a confined space via propelling microdroplets. These microdroplets can form spontaneously from localized liquid-liquid phase separation as a ternary mixture is diluted by a diffusing poor solvent. High speed images reveal how the microdroplets grow, break up and propel rapidly along the solid surface, with a maximal velocity up to ∼160 µm s-1, in response to a sharp concentration gradient resulting from phase separation. The microdroplet propulsion induces a replenishing flow between the walls of the confined space towards the location of phase separation, which in turn drives the mixture out of equilibrium and leads to a repeating cascade of events. Our findings on the complex and rich phenomena of propelling droplets suggest an effective approach to enhanced flow motion of multicomponent liquid mixtures within confined spaces for time effective separation and smart transport processes.

Positive and negative photoconductivity characteristics in CsPbBr3/graphene heterojunction.

Broadband response photodetectors have received great research interest in optical sensing field. Usually, materials with positive photoconductivity (PPC) are general and the lack of negative photoconductivity (NPC) materials limits the application of photoelectric effect, especially in the broadband photodetecting field. Therefore, the finding of NPC materials is very important. Integrating PPC and NPC response into a single device is extremely meaningful to the development of broadband photodetector. In this work, we fabricated CsPbBr3 nanocrystals (NCs)-multilayered graphene heterojunction, which achieved persistent NPC response to ultra violet (300-390 nm) and PPC response to visible light (420-510 nm). The persistent NPC relies on the desorption of H2O vapor, and varies its intensity with the power intensity of laser. The PPC relies on the holes transmission from NCs to graphene. The recombination of NPC and PPC effect provides background knowledge for the development of broadband photodetector.

Aberrant promoter methylation of T-cadherin in sera is associated with a poor prognosis in oral squamous cell carcinoma.

T-cadherin functions as a suppressor gene, which is frequently inactivated by aberrant promoter methylation in several human cancers, but its methylation status in oral squamous cell carcinoma (OSCC) has been scarcely studied. Thus this study aimed at exploring the clinical significance and prognostic value of T-cadherin methylation in sera of patients with OSCC. Methylation-specific PCR (MSP) and bisulfate sequencing PCR (BSP) was performed to examine the methylation status of T-cadherin. Then, the associations between methylation status of T-cadherin and various clinicopathological variables or patient survival were investigated in 202 patients with OSCC and 68 controls. T-cadherin methylation was detected in 62 out of 202 (30.7%) patients with OSCC, and the methylation status of T-cadherin in corresponding tissues was confirmed by BSP. Methylation of T-cadherin was significantly associated with advanced tumor T-stage (p<0.001) and N-stage (p=0.003), positive lymphatic metastasis (p=0.004) and tumor recurrence (p=0.001). In addition, patients with methylation of T-cadherin had worse overall survival (p=0.018) and progression-free survival (p<0.001) than patients without, and methylation of T-cadherin in sera was an independent prognostic factor for worse overall survival (HR: 3.626, 95% CI: 1.112-9.624, p=0.007) and progression-free survival (HR: 4.201, 95% CI: 1.562-10.038, p<0.001) of patients with OSCC. These results demonstrated that methylation of T-cadherin was frequently detected in sera of patients with OSCC, which was associated with risk factors of poor outcomes, and may act as a potential independent prognostic marker for patients with OSCC.

Mechanistic Insight into Energy-Transfer Dynamics and Color Tunability of Na4 CaSi3 O9 :Tb3+ ,Eu3+ for Warm White LEDs.

In this work, a latent energy-transfer process in traditional Eu3+ ,Tb3+ -doped phosphors is proposed and a new class of Eu3+ ,Tb3+ -doped Na4 CaSi3 O9 (NCSO) phosphors is presented which is enabled by luminescence decay dynamics that optimize the electron-transfer energy process. Relative to other Eu3+ ,Tb3+ -doped phosphors, the as-synthesized Eu3+ ,Tb3+ -doped NCSO phosphors show improved large-scale tunable emission color from green to red upon UV excitation, controlled by the Tb3+ /Eu3+ doping ratio. Detailed spectroscopic measurements in the vacuum ultraviolet (VUV)/UV/Vis region were used to determine the Eu3+ -O2- charge-transfer energy, 4f-5d transition energies, and the energies of 4f excited multiplets of Eu3+ and Tb3+ with different 4fN electronic configurations. The Tb3+ →Eu3+ energy-transfer pathway in the co-doped sample was systematically investigated, by employing luminescence decay dynamics analysis to elucidate the relevant energy-transfer mechanism in combination with the appropriate model simulation. To demonstrate their application potential, a prototype white-light-emitting diode (WLED) device was successfully fabricated by using the yellow luminescence NCSO:0.03Tb3+ , 0.05Eu3+ phosphor with high thermal stability and a BaMgAl10 O17 :Eu2+ phosphor in combination with a near-UV chip. These findings open up a new avenue to realize and develop multifunctional high-performance phosphors by manipulating the energy-transfer process for practical applications.

Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 42,910 single pregnancies with different clinical features.

BACKGROUND: Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. METHODS: A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. RESULTS: A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5-10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. CONCLUSION: Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

Dual-Mode Optical Thermometry Design in Lu3Al5O12:Ce3+/Mn4+ Phosphor.

There is a challenge for noncontact temperature-sensing techniques and the related materials, in which a highly reliable contactless thermometer probe with low cost and high sensitivity is in demand. Here, the Lu3Al5O12:Ce3+/Mn4+ phosphor has been designed and prepared for the high-performance fluorescence temperature-sensing application in a novel one-pot, self-redox, solid-state process. Benefiting from the different electron-lattice/phonon interactions of Ce3+ and Mn4+, two distinguishable emission peaks with significantly different temperature responses originating from Ce3+ and Mn4+ are realized. Applying the fluorescence intensity ratio of Mn4+ versus Ce3+ and the decay lifetime of Mn4+ emission as the temperature readout, a dual-mode optical temperature-sensing mechanism was proposed and studied in the temperature range of 100-350 K. The maximum relative sensitivities (Sr) are derived as 4.37 and 3.22% K-1 respectively, as well as a large chromaticity shift visible to naked eyes (ΔE = 153 × 10-3 in 100-350 K) is observed. This is the first report of a Ce3+,Mn4+ co-doped dual-emitting phosphor, and its unique optical thermometric features demonstrate the high potential of Lu3Al5O12:Ce3+/Mn4+ as an accurate and reliable thermometer probe candidate.

Analysis of 4 imaging features in patients with COVID-19.

BACKGROUND: The aim of this was to analyze 4 chest CT imaging features of patients with coronavirus disease 2019 (COVID-19) in Shenzhen, China so as to improve the diagnosis of COVID-19. METHODS: Chest CT of 34 patients with COVID-19 confirmed by the nucleic acid test (NAT) were retrospectively analyzed. Analyses were performed to investigate the pathological basis of four imaging features("feather sign","dandelion sign","pomegranate sign", and "rime sign") and to summarize the follow-up results. RESULTS: There were 22 patients (65.2%) with typical "feather sign"and 18 (52.9%) with "dandelion sign", while few patients had "pomegranate sign" and "rime sign". The "feather sign" and "dandelion sign" were composed of stripe or round ground-glass opacity (GGO), thickened blood vessels, and small-thickened interlobular septa. The "pomegranate sign" was characterized as follows: the increased range of GGO, the significant thickening of the interlobular septum, complicated with a small amount of punctate alveolar hemorrhage. The "rime sign" was characterized by numerous alveolar edemas. Microscopically, the wall thickening, small vascular proliferation, luminal stenosis, and occlusion, accompanied by interstitial infiltration of inflammatory cells, as well as numerous pulmonary interstitial fibrosis and partial hyaline degeneration were observed. Repeated chest CT revealed the mediastinal lymphadenectasis in one patient. Re-examination of the NAT showed another positive anal swab in two patients. CONCLUSION: "Feather sign" and "dandelion sign" were typical chest CT features in patients withCOVID-19; "pomegranate sign" was an atypical feature, and "rime sign" was a severe feature. In clinical work, accurate identification of various chest CT signs can help to improve the diagnostic accuracy of COVID-19 and reduce the misdiagnosis or missed diagnosis rate.