Urinary lumirubin excretion in jaundiced preterm neonates during phototherapy with blue light-emitting diode vs. green fluorescent lamp.

Phototherapy converts lipophilic unconjugated bilirubin to hydrophilic bilirubin photoisomers, such as lumirubin. We comparatively used a blue light-emitting diode (LED) and a green fluorescent lamp (FL) as light sources for phototherapy of hyperbilirubinemic preterm neonates with the aim of examining potential differences in urinary lumirubin excretion between these two wavelengths. Urinary lumirubin levels were measured using a fluorescence assay with blue light exposure in the presence of the unconjugated bilirubin-inducible fluorescent protein UnaG, and denoted as urinary UnaG-bound bilirubin (UUB)/creatinine (Cr) (µg/mg Cr). Preterm neonates born at ≤ 33 weeks gestational age and treated with phototherapy were subjected to this study. The maximum UUB/Cr level during phototherapy per device intensity was compared between neonates treated with the blue LED and the green FL. A total of 61 neonates were examined to determine the maximum UUB/Cr levels. The median of maximum UUB/Cr excretion per light intensity of each device (µg/mg Cr/µW/cm2/nm) was 0.83 for the blue LED and 1.29 for the green FL (p = 0.01). Green light was found to be more effective than blue one for bilirubin excretion via urinary lumirubin excretion. This is the first spectroscopic study to compare the efficacy of phototherapy at different wavelengths using fluorescence assay.

Validation of London Atlas for forensic age estimation in Koreans by comparing with Lee's and Willems' methods.

This cross-sectional study aimed to evaluate the applicability of the London Atlas for age estimation in the Korean population by comparing with Lee's and Willems' methods. Dental ages of 475 orthopantomographs from Korean individuals aged 4-15 years (mean 10.32 ± 3.31 years) were estimated using the London Atlas, Lee's and Willems' methods. Correlation between dental and chronological age was determined using Pearson's correlation coefficient, and the statistical difference between dental and chronological age was analyzed using a paired t-test. The bias (mean differences), mean absolute error, and root mean square error between dental and chronological age, stratified by age groups and estimation methods, were calculated. Differences in bias and absolute error between sexes were scrutinized using an independent-samples t-test. Age estimates of the three tested methods were combined and compared to those of each individual method. The London Atlas and Willems methods resulted in overestimations, whereas the Lee method led to an underestimation on the entire sample. The overall accuracy was observed in the order of Lee's method, the London Atlas, and Willems' method. The London Atlas demonstrated superior consistency of estimation performance across age groups and no significant differences in estimation performance between sexes. The combination of estimates from the London Atlas and Lee's method resulted in an enhancement in bias and accuracy. We conclude that the London Atlas, due to its bias and accuracy comparable to Lee's and Willems' methods, is applicable for forensic practice in the Korean population.

Dental characteristics on panoramic radiographs as parameters for non-invasive age estimation: a pilot study.

The dental characteristics created by acquired dental treatments can be used as age estimators. This pilot study aimed to analyze the correlation between the number of teeth observed for dental characteristics and chronological age and to develop new non-invasive age estimation models. Dental features on panoramic radiographs (420 radiographs of subjects aged 20-89 years) were classified and coded. The correlation between the number of teeth for each selected code (codes V, X, T, F, P, and L) and age was observed, and multiple regression was performed to analyze the relationship between them. Eleven regression models with various combinations of dental sextants were presented. The model with the data from both sides of the posterior teeth on both jaws showed the best performance (root mean square error of 14.78 years and an adjusted R2 of 0.461). The model with all teeth was the second-best. Based on these results, we confirmed statistically significant correlations between certain dental features and chronological age. We also observed that some regression models performed sufficiently well to be used as adjunctive methods in forensic practice. These results provide valuable information for the design and performance of future full-scale studies.

Cardiac Reversibility and Survival After Transcatheter Aortic Valve Implantation in Patients With Low-Gradient Aortic Stenosis.

Background Prognostic implications of transcatheter aortic valve implantation (TAVI) in low-gradient (LG) aortic stenosis (AS) remain controversial. The authors hypothesized that differences in cardiac functional recovery may solve this ongoing controversy. The aim was to evaluate clinical outcomes and the response of left ventricular (LV) function following TAVI in patients with LG AS. Methods and Results This multicenter retrospective study included 1742 patients with severe AS undergoing TAVI between January 2015 and March 2019. Patients were subdivided into low-flow (LF) LG, normal-flow (NF) LG, LF high-gradient, and NF high-gradient AS groups according to the mean gradient of the aortic valve (LG <40 mm Hg) and LV stroke volume index (LF <35 mL/m2). Outcomes and changes in echocardiographic parameters after TAVI were compared between the groups. A total of 227 patients (13%) had reduced ejection fraction, and 486 patients (28%) had LG AS (LF-LG 143 [8%]; NF-LG 343 [20%]). During a median follow-up period of 747 days, 301 patients experienced a composite end point of cardiovascular death and rehospitalization for cardiovascular events, which was higher in the LF-LG and NF-LG groups than in the high-gradient groups. LG AS was independently associated with the primary outcome (hazard ratio, 1.69; P<0.001). Among 1239 patients with follow-up echocardiography, LG AS showed less improvement in the LV mass index and LV end-diastolic volume compared with high-gradient AS after 1 year, while LV recovery was similar between the LF AS and NF AS groups. Conclusions LG AS was associated with poorer outcomes and LV recovery, regardless of flow status after TAVI. Careful evaluation of AS severity may be required in LG AS to provide TAVI within the appropriate time and advanced care afterward.

Rif1 restrains the rate of replication origin firing in Xenopus laevis.

Metazoan genomes are duplicated by the coordinated activation of clusters of replication origins at different times during S phase, but the underlying mechanisms of this temporal program remain unclear during early development. Rif1, a key replication timing factor, inhibits origin firing by recruiting protein phosphatase 1 (PP1) to chromatin counteracting S phase kinases. We have previously described that Rif1 depletion accelerates early Xenopus laevis embryonic cell cycles. Here, we find that in the absence of Rif1, patterns of replication foci change along with the acceleration of replication cluster activation. However, initiations increase only moderately inside active clusters. Our numerical simulations suggest that the absence of Rif1 compresses the temporal program towards more homogeneity and increases the availability of limiting initiation factors. We experimentally demonstrate that Rif1 depletion increases the chromatin-binding of the S phase kinase Cdc7/Drf1, the firing factors Treslin, MTBP, Cdc45, RecQL4, and the phosphorylation of both Treslin and MTBP. We show that Rif1 globally, but not locally, restrains the replication program in early embryos, possibly by inhibiting or excluding replication factors from chromatin.

Validation of data mining models by comparing with conventional methods for dental age estimation in Korean juveniles and young adults.

Teeth are known to be the most accurate age indicators of human body and are frequently applied in forensic age estimation. We aimed to validate data mining-based dental age estimation, by comparing the accuracy of the estimation and classification performance of 18-year thresholds with conventional methods and with data mining-based age estimation. A total of 2657 panoramic radiographs were collected from Koreans and Japanese populations aged 15 to 23 years. They were subdivided into a training and internal test set of 900 radiographs each from Koreans, and an external test set of 857 radiographs from Japanese. We compared the accuracy and classification performance of the test sets from conventional methods with those from the data mining models. The accuracy of the conventional method with the internal test set was slightly higher than that of the data mining models, with a slight difference (mean absolute error < 0.21 years, root mean square error < 0.24 years). The classification performance of the 18-year threshold was also similar between the conventional method and the data mining models. Thus, conventional methods can be replaced by data mining models in forensic age estimation using second and third molar maturity of Korean juveniles and young adults.

Third molar maturity index (I3M) assessment according to different geographical zones: a large multi-ethnic study sample.

Identification of living undocumented individuals highlights the need for accurate, precise, and reproducible age estimation methods, especially in those cases involving minors. However, when their country of origin is unknown, or it can be only roughly estimated, it is extremely difficult to apply assessment policies, procedures, and practices that are accurate and child-sensitive. The main aim of this research is to optimize the correct classification of adults and minors by establishing new cut-off values for four different continents (Africa, America, Asia, and Europe). For this purpose, a vast sample of 10,701 orthopantomographs (OPTs) from four continents was evaluated. For determination and subsequent validation of the new third molar maturity index (I3M) cut-off values by world regions, a cross-validation by holdout method was used and contingency tables (confusion matrices) were generated. The lower third molar maturity indexes, from both left and right side (I3ML and I3MR) and the combination of both sides (I3ML_I3MR) were calculated. The new cut-off values, that aim to differentiate between a minor and an adult, with more than 74.00% accuracy for all populations were as follows (I3ML; I3MR; I3ML_I3MR, respectively): Africa = (0.10; 0.10; 0.10), America = (0.10; 0.09; 0.09), Asia = (0.15; 0.17; 0.14), and Europe = (0.09; 0.09; 0.09). The higher sensitivity (Se) was detected for the I3ML for male African people (91%) and the higher specificity (Sp) of all the parameters (I3ML; I3MR; I3ML_I3MR) for Europeans both male and female (> 91%). The original cut-off value (0.08) is still useful, especially in discriminating individuals younger than 18 years old which is the goal of the forensic methods used for justice.

Percutaneous repair of systemic atrioventricular valve regurgitation with the MitraClip-NT system in congenitally corrected transposition of great arteries.

In a patient with congenitally corrected transposition of the great arteries, dilatation of the atrioventricular valve annulus related to worsening of systemic ventricular function, which worsened systemic atrioventricular valve (SAVV) functional regurgitation. In this article, we report a case of successful transcatheter treatment with MitraClip (Abbott Vascular, Santa Clara, CA, USA) in a 68-year-old female patient with congenitally corrected transposition of the great arteries and severe SAVV failure using imaging modalities. The patient had been hospitalized four times within 8 months, receiving optimal medical therapy for severe SAVV regurgitation and systemic ventricular failure. In this patient, the risk associated with surgery was considered extremely high owing to severe heart failure and liver cirrhosis. We positioned two clips appropriately, side by side, in between the anterior and septal leaflets, guided by computed tomography and three-dimensional echocardiography. The procedure resulted in optimal post-procedural reduction of regurgitation without stenosis, with a good clinical outcome noted at 2-year follow-up. Learning objective: Since surgery for adult congenital heart disease is linked to high risk, we seek less invasive treatment for such patients. In patients with congenital heart disease and severe valve regurgitation, the use of MitraClip (Abbott Vascular, Santa Clara, CA, USA) could be a feasible option for select cases.

Noninvasive monitoring of bilirubin photoisomer excretion during phototherapy.

Lumirubin is the most prevalently excreted hydrophilic bilirubin photoisomer in phototherapy for neonatal jaundice caused by excess hydrophobic unconjugated bilirubin (ZZ-bilirubin). We developed a simple method to estimate the amount of lumirubin by monitoring the reverse photoisomerization of lumirubin to ZZ-bilirubin. Although lumirubin formation was long considered irreversible, exposure to blue light in the presence of the fluorescent protein UnaG, which binds specifically and tightly to ZZ-bilirubin, enables the reverse photoisomerization of lumirubin. This reaction was first detected using a fluorescence assay of neonatal urine sampled during phototherapy and purified lumirubin. The phenomenon of reverse photoisomerization of lumirubin was validated using liquid chromatography-mass spectrometry, which confirmed that lumirubin is reconverted to ZZ-bilirubin in the presence of UnaG. Analyses of 20 urine samples from 17 neonates revealed a significant correlation (correlation coefficient [r] = 0.978; 95% confidence interval 0.867-0.979; P < .001) between lumirubin and ZZ-bilirubin concentration before and after reverse photoisomerization. In general, the rate of photo-reconversion of lumirubin to ZZ-bilirubin is approximately 40%. In conclusion, we demonstrate here that lumirubin can be photo-reconverted to ZZ-bilirubin via exposure to blue light in the presence of UnaG. Utilizing this approach, urinary lumirubin levels can be estimated using an easy-to-perform fluorescence assay.

Accuracy of age estimation and assessment of the 18-year threshold based on second and third molar maturity in Koreans and Japanese.

This study aimed to validate Lee's age estimation method and assess the 18-year threshold in Korean and Japanese populations. We evaluated the maxillary and mandibular second (M2) and third molars (M3) in 2657 orthopantomograms of the Korean and Japanese populations aged 15-23 years (19.47±2.62 years for Koreans, 19.31±2.60 years for Japanese), using Demirjian's criteria. Dental age was estimated, and correlations between chronological and dental ages were analyzed. Classification performance was calculated based on the 18-year threshold. The relationship between developmental stage and chronologic age was analyzed using multiple linear regression. Our results revealed that Lee's method was appropriate for estimation in the Korean population. When the Lee's method was applied to the Japanese population, a lower value of correlation coefficients between estimated and chronological age, and lower specificity were observed. Population differences were observed predominantly in the stages of root development (stages F and G) of M2s and M3s in both jaws and more frequently in females than in males. In the multiple linear regression between developmental stage and chronological age, lower values of adjusted r2 were observed in the Japanese population than in the Koreans. In conclusion, the Lee's method derived from the Korean population data might be unsuitable for Japanese juveniles and adolescents. To support the findings of this study, future studies with samples from multiple institutions should be conducted. Future studies with larger sample sizes are also warranted to improve the accuracy of dental age estimation and confirm the developmental pattern of teeth in the Japanese population.

The applicability of Willems' and Lee's dental age estimation methods for Japanese children and the comparison with the Korean population.

This study aimed to examine the applicability of Willems' and Lee's methods in a Japanese population and to find the differences in teeth development between Japanese and Korean children by comparing the accuracy of their estimated age using the two methods. The developmental status of the lower left permanent teeth in 1,475 orthopantomograms of Japanese children were evaluated based on Demirjian's criteria, and the ages were estimated using Willems' and Lee's methods. The errors in estimated ages were calculated and compared with equivalent Korean population data. The accuracy of both methods for estimating the age of the Japanese population was similar to that in the Korean population except for that of Lee's method used in Japanese males. The results showed that there might be differences in teeth development between the Japanese and Korean boys. To increase the accuracy of the dental age estimation, the method that is derived from their own population data should be applied in forensic practice.

Safety and feasibility of retrograde INOUE-BALLOON for balloon aortic valvuloplasty without rapid ventricular pacing during transcatheter aortic valve replacement.

Rapid ventricular pacing (RVP) is commonly employed during transcatheter aortic valve replacement (TAVR); however, frequent TAVR is associated with worse prognoses. The retrograde INOUE-BALLOON® (IB) allows balloon aortic valvuloplasty (BAV) without RVP. The aim of this study was to evaluate the feasibility of retrograde IB for TAVR preparation. The study population included 178 consecutive patients (mean age, 84 ± 5 years; male, 47%) who underwent retrograde BAV before prosthetic valve replacement via the transfemoral approach. Patients were divided into a retrograde IB group without RVP (n = 74) and a conventional balloon (CB) group with RVP (n = 104). The primary endpoint was prolonged hypotension after BAV (reduced systolic pressure < 80 mmHg for over 1 min or vasopressor drug requirement). The incidence of prolonged hypotension after BAV was significantly lower in the IB group compared with the CB group (4% vs. 16%, p = 0.011). Balloons were able to penetrate and expand the aortic valve in both groups. RVP was used less for total TAVR in the IB group compared with the CB group. The aortic valve area-index after BAV was not significantly different between the two groups (0.72 ± 0.14 cm2/m2 vs. 0.71 ± 0.12 cm2/m2; p = 0.856). Multivariate analysis demonstrated that IB use was associated with avoidance of prolonged hypotension (OR, 0.27 [0.059-0.952]; p = 0.041). In conclusion, BAV using retrograde IB without RVP is both safe and feasible. More stable hemodynamics were achieved using retrograde IB by avoiding RVP during TAVR.

Development and characterization of a unique anti-IgE mouse monoclonal antibody cross-reactive between human and canine IgE.

BACKGROUND: The efficacy assessment of human anti-IgE monoclonal antibodies (mAbs) in animal models before clinical trials is hampered due to the lack of cross-reactivity of anti-IgE mAbs between species. OBJECTIVE: We developed CRE-DR (an anti-dog IgE monoclonal antibody), an anti-IgE mouse mAb that recognizes canine and human IgE, and then examined its IgE specificity and cross-reactivity between three animal and human species. METHODS: After mouse immunization with a synthetic peptide derived from canine IgE (282 NTNDWIEGETYYC294 ), we generated a hybridoma producing CRE-DR. The CRE-DR purified from the ascites of hybridoma-inoculated mice was used for ELISA and Western blot analysis to examine reactivity to dog, human, and rodent IgEs as well as recombinant bovine serum albumin (BSA)-conjugated to canine, human, and rodent IgE amino acid peptides corresponding to the immunizing sequence. We then performed enzyme-linked immunosorbent assays (ELISAs) for dog IgE using sera from dogs with atopic dermatitis (AD) after inhibition with canine IgE and IgG. The amino acid sequence recognized by CRE-DR was identified by ELISA using synthetic peptides. RESULTS: CRE-DR is a monoclonal mouse IgG1κ specific for dog IgE, and the ELISA values in atopic dog sera were inhibited by dog IgE, but not dog IgG. The binding of CRE-DR to human IgE was relatively maintained, but not to rodent IgEs, which results were confirmed with the BSA-conjugated IgE peptides of the various species. The CRE-DR reactivity was supported by the comparison of amino acid sequence of CRE-DR epitope, DWIEGETYYC, in dog IgE; one, two, and three amino acids were substituted in the human, rat, and mouse IgE epitopes, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: CRE-DR is a mAb cross-reactive to dog and human IgEs, which can allow the use of a dog model of allergy to test the efficacy of a CRE-DR-derived anti-IgE therapeutic mAb before human clinical trials.

Effectiveness and limitations of human identification from cremains: A report of two cases.

The present study of two case reports of the victims of the Great East Japan Earthquake demonstrates the effectiveness and limitations of using dental cone-beam computed tomography (CBCT) imaging of cremains as a means of identification. In case 1, identification was assisted by further expanding the age range of the cremains evaluated on macroscopy by obtaining CBCT images of the cremated maxilla. The findings of case 2 presented the possibility that the deceased and the candidate were the same person by superimposing the CBCT images of the cremated patella on the X-ray of the candidate. However, since cremated bones are deformed to varying degrees, it is clear that the images obtained before, rather than after, cremation are more effective in comparing post-mortem and ante-mortem images. Thus, it is necessary to collect extensive and diverse data on the deceased before cremation.

Additive Value of CT to Age, Aortic Diameter, and Echocardiography in Diagnosis and Classification of Bicuspid Aortic Valve in Patients with Severe Aortic Stenosis.

PURPOSE: To develop and validate a CT diagnostic algorithm for bicuspid aortic valve (BAV) classification. MATERIALS AND METHODS: This retrospective study included 212 consecutive patients with severe aortic stenosis who underwent CT followed by aortic valve replacement (mean age, 71 years [range, 27-93 years]; 125 women; 37% with a BAV) from 2012 to 2017. BAV diagnosis and BAV category were determined by using the CT diagnostic algorithm developed and were compared with those attained through surgical diagnosis. Reproducibility and agreement were assessed using the Cohen kappa (κ) coefficient. The value of adding CT to age, aortic diameter index, and transthoracic echocardiography (TTE) was evaluated by using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and decision-curve analysis. RESULTS: Intra- and interobserver reproducibility were good or excellent for all CT diagnoses (κ ≥ 0.6 for all). Agreement between CT and surgical diagnoses was excellent (κ = 0.90) for BAV detection and good (κ = 0.69) for BAV categorization. Sixteen percent (five of 31) of patients with functional BAV diagnosed by using CT received a diagnosis of congenital BAV at surgery. The addition of CT to age, aortic diameter, and TTE showed a higher AUC (with CT, 0.97 [95% CI: 0.91, 0.99] vs without CT, 0.91 [95% CI: 0.85, 0.95]; P = .003) and NRI (1.79 [95% CI: 1.65, 1.92], P < .001) and a higher net benefit among all BAV probabilities. CONCLUSION: CT diagnosis was consistent with surgical diagnosis and had an additive value over traditional diagnostic methods; however, there was a risk of overlooking congenital BAV in patients with functional BAV diagnosed by using CT.Supplemental material is available for this article.© RSNA, 2021.

Eltrombopag in Combination with Rabbit Anti-thymocyte Globulin/Cyclosporine A in Immunosuppressive Therapy-naïve Patients with Aplastic Anemia in Japan.

Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naïve and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan.

Binding of the Treslin-MTBP Complex to Specific Regions of the Human Genome Promotes the Initiation of DNA Replication.

The processes that control where higher eukaryotic cells initiate DNA replication throughout the genome are not understood clearly. In metazoans, the Treslin-MTBP complex mediates critical final steps in formation of the activated replicative helicase prior to initiation of replication. Here, we map the genome-wide distribution of the MTBP subunit of this complex in human cells. Our results indicate that MTBP binds to at least 30,000 sites in the genome. A majority of these sites reside in regions of open chromatin that contain transcriptional-regulatory elements (e.g., promoters, enhancers, and super-enhancers), which are known to be preferred areas for initiation of replication. Furthermore, many binding sites encompass two genomic features: a nucleosome-free DNA sequence (e.g., G-quadruplex DNA or AP-1 motif) and a nucleosome bearing histone marks characteristic of open chromatin, such as H3K4me2. Taken together, these findings indicate that Treslin-MTBP associates coordinately with multiple genomic signals to promote initiation of replication.

Sex-Related Differences in Cardiac Remodeling and Reverse Remodeling After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis in a Japanese Population.

Left ventricular (LV) remodeling with aortic stenosis (AS) appears to differ according to sex, but reverse remodeling after transcatheter aortic valve implantation (TAVI) has not been elucidated in a Japanese population. This study aims to determine whether any sex-related differences in LV or reverse remodeling after TAVI exist in the context of severe AS.Of 208 patients who received TAVI for severe AS in our institution, 100 (men, 42; mean age, 83.0 ± 4.9 years) underwent transthoracic echocardiography before and 3 months after TAVI. Despite similar valvular gradients, women with severe AS had lower indexed LV mass (LVMi) than did men (152.3 ± 35.4 versus 173.2 ± 44.6 g/m2, P = 0.005), with smaller indexed LV end-diastolic (LVEDVi) (50.2 ± 13.3 versus 61.4 ± 20.7 mL/m2, P = 0.001) and end-systolic (LVESVi; 17.9 ± 8.7 versus 24.3 ± 13.8 mL/m2, P = 0.006) volumes. After TAVI, women (-6.0% ± 14.4%) had higher reduction in the rate of change of relative wall thickness (RWT) than did men (4.4% ± 19.0%, P = 0.003). Men (-8.9% ± 3.9%) had higher reduction in the rate of change of LVEDVi than did women (1.5% ± 3.3%, P = 0.045). Incidence of LV reverse remodeling defined as a reduction in LVESV of >15% was significantly higher in men (50%) than in women (26%, P = 0.013).In addition to sex differences in the pattern of LV remodeling with AS, reverse LV remodeling after TAVI also differed between sexes.