STM/TERS observation of (M)-type diphenyl[7]thiaheterohelicene on Ag(111).

The chiral recognition of a self-assembled structure of enantiopure (M)-type 2,13-diphenyl[7]thiaheterohelicene ((M)-Ph-[7]TH) was investigated on a Ag(111) substrate by scanning tunnelling microscopy (STM) and tip-enhanced Raman spectroscopy (TERS). In contrast to previous research of thiaheterohelicene and its derivatives showing zigzag row formation on the Ag(111) substrate, the hexagonal ordered structure was observed by STM. The obtained TERS spectra of (M)-Ph-[7]TH were consistent with the Raman spectra calculated on the basis of density functional theory (DFT), which suggests that (M)-Ph-[7]TH was adsorbed on the substrate without decomposition. The sample bias voltage dependence of STM images combined with the calculated molecular orbitals of (M)-Ph-[7]TH indicates that a phenyl ring was observed as a protrusion at +3.0 V, whereas the helicene backbone was observed at +0.5 V. From these results, a possible model of the hexagonal structure was proposed. Owing to the phenyl ring, the van der Waals interaction between (M)-Ph-[7]TH and the substrate becomes strong. This leads to the formation of the hexagonal structure with the same symmetry as the substrate.

Single-Cell RNA Sequencing of Arabidopsis Leaf Tissues Identifies Multiple Specialized Cell Types: Idioblast Myrosin Cells and Potential Glucosinolate-Producing Cells.

The glucosinolate-myrosinase defense system (GMDS), characteristic of Brassicales, is involved in plant defense. Previous single-cell transcriptomic analyses have reported the expression profiles of multiple GMDS-related cell types (i.e. myrosinase-rich myrosin idioblasts and multiple types of potential glucosinolate synthetic cells as well as a candidate S-cell for glucosinolate accumulation). However, differences in plant stages and cell-type annotation methods have hindered comparisons among studies. Here, we used the single-cell transcriptome profiles of extended Arabidopsis leaves and verified the distribution of previously used markers to refine the expression profiles of GMDS-associated cell types. Moreover, we performed beta-glucuronidase promoter assays to confirm the histological expression patterns of newly obtained markers for GMDS-associated candidates. As a result, we found a set of new specific reporters for myrosin cells and potential glucosinolate-producing cells.

Defining the observable processes of patient care related to social determinants of health.

INTRODUCTION: An understanding of social determinants of health (SDH) and patients' social circumstances is recommended to deliver contextualised care. However, the processes of patient care related to SDH in clinical settings have not been described in detail. Observable practice activities (OPAs) are a collection of learning objectives and activities that must be observed in daily practice and can be used to describe the precise processes for professionals to follow in specific situations (process OPA.) METHODS: We used a modified Delphi technique to generate expert consensus about the process OPA for patient care related to SDH in primary care settings. To reflect the opinions of various stakeholders, the expert panel comprised clinical professionals (physicians, nurses, public health nurses, social workers, pharmacists and medical clerks), residents, medical students, researchers (medical education, health care, sociology of marginalised people), support members for marginalised people and patients. The Delphi rounds were conducted online. In Round 1, a list of potentially important steps in the processes of care was distributed to panellists. The list was modified, and one new step was added. In Round 2, all steps were acknowledged with few modifications. RESULTS: Of 63 experts recruited, 61 participated, and all participants completed the Delphi rounds. A total of 14 observable steps were identified, which were divided into four components: communication, practice, maintenance and advocacy. The importance of ongoing patient-physician relationships and collaboration with professionals and stakeholders was emphasised for the whole process of care. DISCUSSION: This study presents the consensus of a variety of experts on the process OPA for patient care related to SDHs. Further research is warranted to investigate how this Communication-Practice-Maintenance-Advocacy framework could affect medical education, quality of patient care, and patient outcomes.

Ceusia-Breast: computer-aided diagnosis with contrast enhanced ultrasound image analysis for breast lesions.

BACKGROUND: In recent years, contrast-enhanced ultrasonography (CEUS) has been used for various applications in breast diagnosis. The superiority of CEUS over conventional B-mode imaging in the ultrasound diagnosis of the breast lesions in clinical practice has been widely confirmed. On the other hand, there have been many proposals for computer-aided diagnosis of breast lesions on B-mode ultrasound images, but few for CEUS. We propose a semi-automatic classification method based on machine learning in CEUS of breast lesions. METHODS: The proposed method extracts spatial and temporal features from CEUS videos and breast tumors are classified as benign or malignant using linear support vector machines (SVM) with combination of selected optimal features. In the proposed method, tumor regions are extracted using the guidance information specified by the examiners, then morphological and texture features of tumor regions obtained from B-mode and CEUS images and TIC features obtained from CEUS video are extracted. Then, our method uses SVM classifiers to classify breast tumors as benign or malignant. During SVM training, many features are prepared, and useful features are selected. We name our proposed method "Ceucia-Breast" (Contrast Enhanced UltraSound Image Analysis for BREAST lesions). RESULTS: The experimental results on 119 subjects show that the area under the receiver operating curve, accuracy, precision, and recall are 0.893, 0.816, 0.841 and 0.920, respectively. The classification performance is improved by our method over conventional methods using only B-mode images. In addition, we confirm that the selected features are consistent with the CEUS guidelines for breast tumor diagnosis. Furthermore, we conduct an experiment on the operator dependency of specifying guidance information and find that the intra-operator and inter-operator kappa coefficients are 1.0 and 0.798, respectively. CONCLUSION: The experimental results show a significant improvement in classification performance compared to conventional classification methods using only B-mode images. We also confirm that the selected features are related to the findings that are considered important in clinical practice. Furthermore, we verify the intra- and inter-examiner correlation in the guidance input for region extraction and confirm that both correlations are in strong agreement.

Impact of value similarity on social trust in medical students: a cross-sectional web survey.

BACKGROUND: Social trust in medical students is trust in the cluster of medical students and not individual medical students. Social trust in medical students seems critical in clinical practice since citizens often face unknown medical students for the first time. However, most previous research has focused on interpersonal trust in particular medical professions, and social trust in medical students has not been addressed sufficiently. In social science, the Salient Value Similarity model has demonstrated that the value similarity between professionals and citizens is associated with social trust. This research aimed to explore the relationship between social trust in medical students and the perception of value similarity. This study also aimed to determine whether the information of medical students strengthens social trust in them. METHODS: We conducted a cross-sectional study to investigate how the perception of value similarity affects social trust. The participants answered the social trust questionnaires before and after reading a brief summary of the medical education curriculum and certification via the internet in Japan. The model structure of social trust in medical students, including the perception of value similarity, was investigated using SEM. A paired t-test was used to examine the effect of informing citizens about the knowledge, skills, and professionalism requirements of students attending medical school on social trust by reading the brief summary. RESULTS: The study included 658 participants, who all answered a web questionnaire. Social trust in medical students was associated with the perception of ability and value similarity. Social trust in medical students, the perception of ability, and value similarity were improved by information about medical students. CONCLUSIONS: The perception of ability and value similarity seem to affect social trust in medical students. Information on medical education regarding the knowledge, skills, and professionalism of medical students may improve social trust in these students. Further research is required to sophisticate the model of social trust in medical students by exploring social trust in the medical students' supervisors in clinical settings.

A qualitative study examining the critical differences in the experience of and response to formative feedback by undergraduate medical students in Japan and the UK.

BACKGROUND: Formative feedback plays a critical role in guiding learners to gain competence, serving as an opportunity for reflection and feedback on their learning progress and needs. Medical education in Japan has historically been dominated by a summative paradigm within assessment, as opposed to countries such as the UK where there are greater opportunities for formative feedback. How this difference affects students' interaction with feedback has not been studied. We aim to explore the difference in students' perception of feedback in Japan and the UK. METHODS: The study is designed and analysed with a constructivist grounded theory lens. Medical students in Japan and the UK were interviewed on the topic of formative assessment and feedback they received during clinical placements. We undertook purposeful sampling and concurrent data collection. Data analysis through open and axial coding with iterative discussion among research group members was conducted to develop a theoretical framework. RESULTS: Japanese students perceived feedback as a model answer provided by tutors which they should not critically question, which contrasted with the views of UK students. Japanese students viewed formative assessment as an opportunity to gauge whether they are achieving the pass mark, while UK students used the experience for reflective learning. CONCLUSIONS: The Japanese student experience of formative assessment and feedback supports the view that medical education and examination systems in Japan are focused on summative assessment, which operates alongside culturally derived social pressures including the expectation to correct mistakes. These findings provide new insights in supporting students to learn from formative feedback in both Japanese and UK contexts.

Development and assessment of a vaccine administration training course for medical students.

BACKGROUND: Vaccine administration skills are very important for physicians, especially in the era of global pandemics. However, medical students have reported that practical sessions to develop these skills are insufficient. Therefore, the aim of our study was to develop a vaccination training course for medical students. We also examined its educational effectiveness. METHODS: 5th- and 6th-year medical students at the University of Tokyo were recruited to attend the vaccine administration training course in 2021. These students were our study participants. Our course consisted of an orientation part, which included a lecture on the indications, adverse events, and vaccination techniques of flu vaccines and practice on a simulator, and a main part in which the staff of the University of Tokyo Hospital were actually vaccinated. Before and after the main part of the course, study participants completed an online questionnaire that assessed their confidence in vaccine administration technique through a five-point Likert scale. We also surveyed their feedback about the course content and process. At the beginning and end of the main part, their technical competence in vaccination was assessed by two independent doctors. These doctors used a validated checklist scale (ranging from 16 to 80) and a global rating scale (ranging from 0 to 10). We used their mean scores for analysis. The quantitative data were analyzed through the Wilcoxon signed-rank test. For the qualitative data of the questionnaire, thematic analysis was conducted. RESULTS: All 48 course participants participated in our study. Participants' confidence in vaccination technique (Z = -5.244, p < 0.05) and vaccination skill significantly improved (checklist rating: Z = -5.852, p < 0.05; global rating: Z = -5.868, p < 0.05). All participants rated the course as, "overall educational." Our thematic analysis identified four emerging themes: interest in medical procedures, efficacy of supervision and feedback, efficacy of "near-peer" learning, and very instructive course. CONCLUSIONS: In our study, we developed a vaccine administration course for medical students, assessed their vaccination techniques and confidence in those techniques, and investigated their perceptions of the course. Students' vaccination skills and confidence improved significantly after the course, and they positively evaluated the course based on a variety of factors. Our course will be effective in educating medical students about vaccination techniques.

Long-term safety of eldecalcitol in Japanese patients with osteoporosis: a retrospective, large-scale database study.

INTRODUCTION: This real-world study evaluated whether long-term use of eldecalcitol (ELD) increases the risk of adverse events (AEs), namely, hypercalcemia, acute kidney injury (AKI), and urolithiasis, and analyzed the ELD-induced risk of rare AEs such as osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF). MATERIALS AND METHODS: Patient records were retrieved from Medical Data Vision (MDV) and Japan Medical Data Center (JMDC) databases. The ELD-treated osteoporosis patient cohort (ELD cohort) was analyzed to determine the incidence rate of the aforementioned AEs. The patient cohort that was prescribed active vitamin D3 other than ELD (AVD cohort) was analyzed as the reference. RESULTS: Incidence rates of hypercalcemia, AKI, and urolithiasis in the ELD cohort were 0.942, 0.517, 2.465 events per 100 person-years, respectively, in the MDV dataset, and 0.687, 0.155, 3.785, respectively, in the JMDC dataset. The incidence rates of these AEs in the ELD cohort remained relatively constant throughout ELD treatment. A small number of patients experienced ONJ or AFF during ELD or AVD treatment. The number of ONJ and AFF cases in the both cohorts decreased over time. The two cohorts showed no difference in the concomitant use of anti-bone resorptive agents such as bisphosphonates and denosumab. CONCLUSION: The risk of hypercalcemia and AKI associated with ELD use observed in this retrospective analysis is similar to that reported previously in the Japanese post-marketing surveillance of ELD. Furthermore, ELD, similar to AVD, may not increase the risk of ONJ and AFF.

The costochondral length in patients with pectus excavatum is longer than that of the normal thorax.

PURPOSE: Recently, several investigators reported that costal cartilage does not overgrow in pectus excavatum (PE). We wished to clarify whether costochondral length is longer in PE than the normal thorax and we tried to clarify the change of the shape of precordial concavity according to the growth in PE. METHODS: We evaluated 243 CT axial images of patients with PE and 246 CT axial images of patients without thoracic deformity. We divided the fifth costal cartilage into several lengths. We considered each part to be a straight line and calculated the length of the lines. We compared the approximate costochondral length between PE and normal thorax. We analyzed the distance between both anterior tips of fifth rib, and the ratio of the width and the depth of concavity to thoracic diameter in PE. CONCLUSIONS: The costochondral length in patients with PE is highly likely to be longer than that of the normal thorax. The length of costal cartilage may be longer in asymmetric PE than symmetric PE. It may start in infantile period in PE that the thoracic shape turns into asymmetry from symmetry. The precordial concavity of PE may be shaped by overgrowth of both costal cartilages and ribs.

The safety and effectiveness profile of eldecalcitol in a prospective, post-marketing observational study in Japanese male patients with osteoporosis.

We conducted a post-marketing observational study to investigate the safety and effectiveness of eldecalcitol for the treatment of osteoporosis in a Japanese clinical setting. The observation period was 12 months for women and 36 months for men. The final results for the female patients have already been published. In this article, the final results for the male patients are reported. A total of 470 male osteoporosis patients were enrolled. The safety analysis set included 431 patients (mean age, 76.8 years; mean ± SD follow-up period, 631.0 ± 450.3 days), and 175 patients continued treatment throughout the 3-year observational period. Adverse drug reactions (ADRs) were reported in 28 patients (6.49%); the most common ADRs were hypercalcemia (1.16%) and renal impairment (1.16%). Serious ADRs were reported in 5 patients (1.16%). Mean serum calcium was within the normal range throughout the observation period. The cumulative incidence of new vertebral and nonvertebral fractures at 36 months, estimated by Kaplan-Meier analysis, was 10.23 and 4.06%, respectively. At the last observation, mean lumbar spine bone mineral density was 3.49% higher (P < 0.0001) than at baseline, and levels of the bone turnover markers BAP and TRACP-5b were reduced (-14.64%; P = 0.0009, and - 29.51%; P < 0.0001, respectively). In conclusion, the safety and effectiveness of eldecalcitol for the treatment of Japanese male osteoporosis patients was confirmed in clinical practice. Careful monitoring of serum calcium and estimated glomerular filtration rate, both before and during treatment, is necessary to minimize the risk of hypercalcemia and renal impairment while maximizing the effectiveness of eldecalcitol.

Using human iPS cell-derived enterocytes as novel in vitro model for the evaluation of human intestinal mucosal damage.

OBJECTIVE AND DESIGN: The primary component in gut mucus is mucin 2 (MUC2) secreted by goblet cells. Fluctuations in MUC2 expression are considered a useful indicator for evaluating mucosal damage and protective effect of various agents using animal studies. However, there are few in vitro studies evaluating mucosal damage using MUC2 as the indicator. Hence, we attempted to establish a novel in vitro model with MUC2 as the indicator for evaluating drug-induced mucosal damage and protective effect using enterocytes derived from human iPS cells. METHODS: Compounds were added into enterocytes derived from human iPS cells, and MUC2 mRNA and protein expression levels were evaluated. Further, the effect of compounds on membrane permeability was investigated. RESULTS: Nonsteroidal anti-inflammatory drugs were found to decrease MUC2 mRNA expression in enterocytes, whereas mucosal protective agents increased mRNA levels. Changes in MUC2 protein expression were consistent with those of mRNA. Additionally, our results indicated that indomethacin caused mucosal damage, affecting membrane permeability of the drug. Moreover, we observed protective effect of rebamipide against the indomethacin-induced permeability increase. CONCLUSIONS: The developed model could facilitate evaluating drug-induced mucosal damage and protective effects of various agents and could impact drug development studies regarding pharmacological efficacy and safety.

Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes.

The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4.

Overexpression of a novel Arabidopsis PP2C isoform, AtPP2CF1, enhances plant biomass production by increasing inflorescence stem growth.

In contrast to mammals, higher plants have evolved to express diverse protein phosphatase 2Cs (PP2Cs). Of all Arabidopsis thaliana PP2Cs, members of PP2C subfamily A, including ABI1, have been shown to be key negative regulators of abscisic acid (ABA) signalling pathways, which regulate plant growth and development as well as tolerance to adverse environmental conditions. However, little is known about the enzymatic and signalling roles of other PP2C subfamilies. Here, we report a novel Arabidopsis subfamily E PP2C gene, At3g05640, designated AtPP2CF1. AtPP2CF1 was dramatically expressed in response to exogenous ABA and was expressed in vascular tissues and guard cells, similar to most subfamily A PP2C genes. In vitro enzymatic activity assays showed that AtPP2CF1 possessed functional PP2C activity. However, yeast two-hybrid analysis revealed that AtPP2CF1 did not interact with PYR/PYL/RCAR receptors or three SnRK2 kinases, which are ABI1-interacting proteins. This was supported by homology-based structural modelling demonstrating that the putative active- and substrate-binding site of AtPP2CF1 differed from that of ABI1. Furthermore, while overexpression of ABI1 in plants induced an ABA-insensitive phenotype, Arabidopsis plants overexpressing AtPP2CF1 (AtPP2CF1oe) were weakly hypersensitive to ABA during seed germination and drought stress. Unexpectedly, AtPP2CF1oe plants also exhibited increased biomass yield, mainly due to accelerated growth of inflorescence stems through the activation of cell proliferation and expansion. Our results provide new insights into the physiological significance of AtPP2CF1 as a candidate gene for plant growth production and for potential application in the sustainable supply of plant biomass.

Development of a Subtraction Processing Technology for Assistance in the Comparative Interpretation of Mammograms.

A comparative interpretation of mammograms has become increasingly important, and it is crucial to develop subtraction processing and registration methods for mammograms. However, nonrigid image registration has seldom been applied to subjects constructed with soft tissue only, such as mammograms. We examined whether subtraction processing for the comparative interpretation of mammograms can be performed using nonrigid image registration. As a preliminary study, we evaluated the results of subtraction processing by applying nonrigid image registration to normal mammograms, assuming a comparative interpretation between the left and right breasts. Mediolateral-oblique-view mammograms were taken from noncancer patients and divided into 1000 cases for training, 100 cases for validation, and 500 cases for testing. Nonrigid image registration was applied to align the horizontally flipped left-breast mammogram with the right one. We compared the sum of absolute differences (SAD) of the difference of bilateral images (Difference Image) with and without the application of nonrigid image registration. Statistically, the average SAD was significantly lower with the application of nonrigid image registration than without it (without: 0.0692; with: 0.0549 (p < 0.001)). In four subgroups using the breast area, breast density, compressed breast thickness, and Difference Image without nonrigid image registration, the average SAD of the Difference Image was also significantly lower with nonrigid image registration than without it (p < 0.001). Nonrigid image registration was found to be sufficiently useful in aligning bilateral mammograms, and it is expected to be an important tool in the development of a support system for the comparative interpretation of mammograms.

Identifying factors that indicate the possibility of non-visible cases on mammograms using mammary gland content ratio estimated by artificial intelligence.

Background: Mammography is the modality of choice for breast cancer screening. However, some cases of breast cancer have been diagnosed through ultrasonography alone with no or benign findings on mammography (hereby referred to as non-visibles). Therefore, this study aimed to identify factors that indicate the possibility of non-visibles based on the mammary gland content ratio estimated using artificial intelligence (AI) by patient age and compressed breast thickness (CBT). Methods: We used AI previously developed by us to estimate the mammary gland content ratio and quantitatively analyze 26,232 controls and 150 non-visibles. First, we evaluated divergence trends between controls and non-visibles based on the average estimated mammary gland content ratio to ensure the importance of analysis by age and CBT. Next, we evaluated the possibility that mammary gland content ratio ≥50% groups affect the divergence between controls and non-visibles to specifically identify factors that indicate the possibility of non-visibles. The images were classified into two groups for the estimated mammary gland content ratios with a threshold of 50%, and logistic regression analysis was performed between controls and non-visibles. Results: The average estimated mammary gland content ratio was significantly higher in non-visibles than in controls when the overall sample, the patient age was ≥40 years and the CBT was ≥40 mm (p < 0.05). The differences in the average estimated mammary gland content ratios in the controls and non-visibles for the overall sample was 7.54%, the differences in patients aged 40-49, 50-59, and ≥60 years were 6.20%, 7.48%, and 4.78%, respectively, and the differences in those with a CBT of 40-49, 50-59, and ≥60 mm were 6.67%, 9.71%, and 16.13%, respectively. In evaluating mammary gland content ratio ≥50% groups, we also found positive correlations for non-visibles when controls were used as the baseline for the overall sample, in patients aged 40-59 years, and in those with a CBT ≥40 mm (p < 0.05). The corresponding odds ratios were ≥2.20, with a maximum value of 4.36. Conclusion: The study findings highlight an estimated mammary gland content ratio of ≥50% in patients aged 40-59 years or in those with ≥40 mm CBT could be indicative factors for non-visibles.

Spirometry test values can be estimated from a single chest radiograph.

Introduction: Physical measurements of expiratory flow volume and speed can be obtained using spirometry. These measurements have been used for the diagnosis and risk assessment of chronic obstructive pulmonary disease and play a crucial role in delivering early care. However, spirometry is not performed frequently in routine clinical practice, thereby hindering the early detection of pulmonary function impairment. Chest radiographs (CXRs), though acquired frequently, are not used to measure pulmonary functional information. This study aimed to evaluate whether spirometry parameters can be estimated accurately from single frontal CXR without image findings using deep learning. Methods: Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC as spirometry measurements as well as the corresponding chest radiographs of 11,837 participants were used in this study. The data were randomly allocated to the training, validation, and evaluation datasets at an 8:1:1 ratio. A deep learning network was pretrained using ImageNet. The input and output information were CXRs and spirometry test values, respectively. The training and evaluation of the deep learning network were performed separately for each parameter. The mean absolute error rate (MAPE) and Pearson's correlation coefficient (r) were used as the evaluation indices. Results: The MAPEs between the spirometry measurements and AI estimates for FVC, FEV1 and FEV1/FVC were 7.59% (r = 0.910), 9.06% (r = 0.879) and 5.21% (r = 0.522), respectively. A strong positive correlation was observed between the measured and predicted indices of FVC and FEV1. The average accuracy of >90% was obtained in each estimation of spirometry indices. Bland-Altman analysis revealed good agreement between the estimated and measured values for FVC and FEV1. Discussion: Frontal CXRs contain information related to pulmonary function, and AI estimation performed using frontal CXRs without image findings could accurately estimate spirometry values. The network proposed for estimating pulmonary function in this study could serve as a recommendation for performing spirometry or as an alternative method, suggesting its utility.

Domain generalization across tumor types, laboratories, and species - Insights from the 2022 edition of the Mitosis Domain Generalization Challenge.

Recognition of mitotic figures in histologic tumor specimens is highly relevant to patient outcome assessment. This task is challenging for algorithms and human experts alike, with deterioration of algorithmic performance under shifts in image representations. Considerable covariate shifts occur when assessment is performed on different tumor types, images are acquired using different digitization devices, or specimens are produced in different laboratories. This observation motivated the inception of the 2022 challenge on MItosis Domain Generalization (MIDOG 2022). The challenge provided annotated histologic tumor images from six different domains and evaluated the algorithmic approaches for mitotic figure detection provided by nine challenge participants on ten independent domains. Ground truth for mitotic figure detection was established in two ways: a three-expert majority vote and an independent, immunohistochemistry-assisted set of labels. This work represents an overview of the challenge tasks, the algorithmic strategies employed by the participants, and potential factors contributing to their success. With an F1 score of 0.764 for the top-performing team, we summarize that domain generalization across various tumor domains is possible with today's deep learning-based recognition pipelines. However, we also found that domain characteristics not present in the training set (feline as new species, spindle cell shape as new morphology and a new scanner) led to small but significant decreases in performance. When assessed against the immunohistochemistry-assisted reference standard, all methods resulted in reduced recall scores, with only minor changes in the order of participants in the ranking.

AIROGS: Artificial Intelligence for Robust Glaucoma Screening Challenge.

The early detection of glaucoma is essential in preventing visual impairment. Artificial intelligence (AI) can be used to analyze color fundus photographs (CFPs) in a cost-effective manner, making glaucoma screening more accessible. While AI models for glaucoma screening from CFPs have shown promising results in laboratory settings, their performance decreases significantly in real-world scenarios due to the presence of out-of-distribution and low-quality images. To address this issue, we propose the Artificial Intelligence for Robust Glaucoma Screening (AIROGS) challenge. This challenge includes a large dataset of around 113,000 images from about 60,000 patients and 500 different screening centers, and encourages the development of algorithms that are robust to ungradable and unexpected input data. We evaluated solutions from 14 teams in this paper and found that the best teams performed similarly to a set of 20 expert ophthalmologists and optometrists. The highest-scoring team achieved an area under the receiver operating characteristic curve of 0.99 (95% CI: 0.98-0.99) for detecting ungradable images on-the-fly. Additionally, many of the algorithms showed robust performance when tested on three other publicly available datasets. These results demonstrate the feasibility of robust AI-enabled glaucoma screening.

Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma.

Our neuroblastoma cDNA project previously identified Src homology 2 domain containing F (Shf) as one of the genes expressed at high levels in favorable neuroblastoma. Shf is an adaptor protein containing four putative tyrosine phosphorylation sites and an SH2 domain. In this study, we found that Shf interacted with anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase in neuroblastoma. Real-time PCR analysis showed that Shf mRNA is highly expressed in non-metastatic neuroblastomas compared to metastatic tumor samples (P < 0.030, n = 106). Interestingly, patients showing high ALK and low Shf mRNA expressions showed poor prognosis, whereas low ALK and high Shf expressions were related to better prognosis (P < 0.023, n = 38). Overexpression of ALK and siRNA-mediated knockdown of Shf yielded similar results, such as an increase in cellular growth and phosphorylation of ALK, in addition to Erk1/2 and signal transducer and activator of transcription 3 (STAT3) that are downstream signals of the ALK-initiated phospho-transduction pathway. Knockdown of Shf also increased the cellular mobility and invasive capability of neuroblastoma cells. These results suggest that Shf interacts with ALK and negatively regulates the ALK-initiated signal transduction pathway in neuroblastoma. We thus propose that Shf inhibits phospho-transduction signals mediated by ALK, which is one of the major key players on neuroblastoma development, resulting in better prognosis of the tumor.