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Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. The unique function of the epithelial cells synthesizing crystallites and assembling them in a mechanically robust structure is not fully elucidated yet, partly due to limitations with in vitro experimental models. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When transplanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model to study mineralization process by dental epithelium, which can pave the way to understanding amelogenesis and developing regenerative therapy of enamel.

Solute segregation to planar defects in metallic alloys has been shown to drastically alter mechanical properties. While various works using first-principles and thermodynamic calculations have studied the fundamental driving forces for solute segregation via the Suzuki criterion, planar defect energy, or a comparison of energies of the HCP-like phase and FCC matrix, a quantitative experimental and computational comparison of equilibrium composition and segregation enthalpies has not yet been reported. In this work, we predict the equilibrium composition and segregation enthalpy to intrinsic stacking faults in a Ni-60Co (at.%) alloy and compare the results to two independent experimental methods. We observed that Co segregates to the innermost two planes of the intrinsic stacking fault, and we found that the experimental segregation enrichment, measured from transmission electron microscopy energy dispersive X-ray spectroscopy, of the faults is 6.8 at.% Co, which is 2.2 at.% less than the predicted value at the same temperature. We also find that the segregation enthalpy measured from the composition profile is −21.1 ± 6.4 meV/atom and separately from differential scanning calorimetry segregation enthalpy is −33.2 meV/atom, whereas the predicted enthalpy is −31 ± 1 meV/atom. Based on these results, we determine that segregation occurs very rapidly, within 8 min at temperatures as low as 36% of the homologous solidus temperature. Furthermore, this analysis provides an overview of the possible dislocation mechanisms responsible for strengthening effects due to solute segregation, and concludes that changes in room temperature hardness from local phase transformation is likely tied to post-segregation room temperature equilibrium partial separation distance. Suzuki segregation involves solute diffusing to and from planar defects in crystals, changing mechanical behavior. Here, theoretical calculations predict cobalt segregation enthalpy in a Ni-Co alloy, validated via atomic-scale spectroscopy and calorimetry, and effect on strengthening.

Objective The coronavirus disease 2019 (COVID-19) pandemic has reduced the demand for, and supply of, head and neck cancer services. This study compares the times to diagnosis, staging, and treatment of head and neck cancers before and during the COVID-19 pandemic. Study Design Retrospective cohort study. Setting Tertiary academic medical center in New York City (NYC). Methods The times to diagnosis, staging, and treatment of head and neck cancer for patients presenting to the clinics of 4 head and neck oncology surgeons with newly diagnosed head and neck cancers were compared between pre–COVID-19 and COVID-19 periods. Results Sixty-eight patients in the pre–COVID-19 period and 26 patients in the COVID-19 period presented with newly diagnosed head and neck cancer. Patients in the COVID-19 group had a significantly longer time to diagnosis than the pre–COVID-19 group after adjustment for age and cancer diagnosis (P = .02; hazard ratio [HR], 0.54; 95% CI, 0.32-0.92). Patients in the pre–COVID-19 and COVID-19 groups had no statistically significant differences in time to staging (P > .9; HR, 1.01; 95% CI, 0.58-1.74) or time to treatment (P = .12; HR, 1.55; 95% CI, 0.89-2.72). Conclusion This study found that time to diagnosis for head and neck cancers was delayed during a COVID-19 period compared to a pre–COVID-19 period. However, there was no evidence of delays in time to staging and time to treatment during the COVID-19 period. Our results prompt further investigations into the factors contributing to diagnostic delays but provide reassurance that despite COVID-19, patients were receiving timely staging and treatment for head and neck cancers.

Background: Transition to adult-centered care requires adolescents with inflammatory bowel disease (IBD) to acquire a set of independent self-management skills. Transition success can be affected by maturity, cognitive development, and many other factors. Our hypothesis was that parenting style would be associated with increased self-efficacy and therefore transitions readiness. Methods: A prospective cohort survey study of adolescents with IBD and their parents from October 2018 to October 2019 was performed. Participants completed the IBD-Self-Efficacy Scale- Adolescent questionnaire (IBD-SES-A) and the Transition Readiness Assessment Questionnaire (TRAQ). Parents completed the Parent Styles and Dimensions Questionnaire (PSDQ-short form). Demographic and disease information were also collected. Results: Sixty-nine participants were included for full analysis (36 males and 33 females); mean age was 18.2 years, and average age of IBD diagnosis 13 years. Overall, 83% of participants were non-Hispanic Caucasian, and 84% reported parental annual income over USD 100,000. All 69 parents reported an authoritative parenting style. Females have significantly higher TRAQ scores than males (p = 0.0004). TRAQ scores differed significantly between age groups, with 20 to 22 years old having higher scores (p ≤ 0.0001). TRAQ and IBD-SES-A scores did not differ by parental education or parenting style. Conclusion: Given the inability to delineate different parenting, this study was unable to demonstrate a protective parenting style associated with better transitions readiness and self-efficacy scores in adolescents with IBD. Within the context of authoritative parenting, we did find that females and older adolescents had higher transition readiness scores. Additional research into psychosocial determinants of transition readiness, and the importance of multidisciplinary management with an integrated team including psychologist and social workers, can help improve IBD transition outcomes.

Quantitation of androgen receptor variant (AR-V) expression in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) has great potential for treatment customization. However, the absence of a uniform CTC isolation platform and consensus on an analytical assay has prevented the incorporation of these measurements in routine clinical practice. Here, we present a single-CTC sensitive digital droplet PCR (ddPCR) assay for the quantitation of the two most common AR-Vs, AR-V7, and AR-v567es, using antigen agnostic CTC enrichment. In a cohort of 29 mCRPC patients, we identify AR-V7 in 66% and AR-v567es in 52% of patients. These results are corroborated using another gene expression platform (NanoStringTM) and by analysis of RNA-Seq data from patients with mCRPC (SU2C- PCF Dream Team). We next quantify AR-V expression in matching EpCAM-positive vs EpCAM-negative CTCs, as EpCAM-based CTC enrichment is commonly used. We identify lower AR-V prevalence in the EpCAM-positive fraction, suggesting that EpCAM-based CTC enrichment likely underestimates AR-V prevalence. Lastly, using single CTC analysis we identify enrichment for AR-v567es in patients with neuroendocrine prostate cancer (NEPC) indicating that AR-v567es may be involved in lineage plasticity, which warrants further mechanistic interrogation.Ada Gjyrezi et al. show that ddPCR can be used to accurately measure androgen receptor variant (AR-V) expression levels in single circulating tumor cells (CTCs) from prostate cancer patients. They show that current methods for isolating CTCs tend to underestimate the prevalence of AR-V and that a specific variant, AR-v567es, could be potentially used as a biomarker for an aggressive subtype of prostate cancer.

BackgroundHeart rate (HR) is used to guide interventions during delivery room (DR) neonatal resuscitation. Dry electrode ECG (NeoBeat) may detect HR more rapidly than pulse oximetry (PO) and portable ECG, but real-time comparisons of these devices are lacking.Design/methodsPO, ECG and NeoBeat were placed sequentially on newborns in the DR. Time for device placement and time to accurate HR acquisition were noted.ResultsDR resuscitations of 28 preterm/term infants were observed. The NeoBeat was placed faster (ie, 3 s) than PO (20 s, p=<0.0001) and ECG (16 s, p=<0.0001). Total time from initiation of device placement to HR acquisition was fastest with NeoBeat (13 s) versus ECG (42 s, p<0.0001) and PO (105 s, p<0.0001) (duration values=median).ConclusionsThese observations in a small cohort of relatively well neonates demonstrate that the NeoBeat is significantly faster to place and consistently acquires HR faster than PO and ECG.

Objective Self‐efficacy, the internal belief that one can perform a specific task successfully, influences behavior. To promote critical appraisal of medical literature, rheumatology training programs should foster both competence and self‐efficacy for critical appraisal. This study aimed to investigate whether select items from the Clinical Research Appraisal Inventory (CRAI), an instrument measuring clinical research self‐efficacy, could be used to measure critical appraisal self‐efficacy (CASE). Methods One hundred twenty‐five trainees from 33 rheumatology programs were sent a questionnaire that included two sections of the CRAI. Six CRAI items relevant to CASE were identified a priori; responses generated a CASE score (total score range 0‐10; higher = greater confidence in one's ability to perform a specific task successfully). CASE scores' internal structure and relation to domain‐concordant variables were analyzed. Results Questionnaires were completed by 112 of 125 (89.6%) trainees. CASE scores ranged from 0.5 to 8.2. The six CRAI items contributing to the CASE score demonstrated high internal consistency (Cronbach's α = 0.95) and unidimensionality. Criterion validity was supported by the findings that participants with higher CASE scores rated their epidemiology and biostatistics understanding higher than that of peers (P < 0.0001) and were more likely to report referring to studies to answer clinical questions (odds ratio 2.47, 95% confidence interval 1.41‐4.33; P = 0.002). The correlation of CASE scores with percentage of questions answered correctly was only moderate, supporting discriminant validity. Conclusion The six‐item CASE instrument demonstrated content validity, internal consistency, discriminative capability, and criterion validity, including correlation with self‐reported behavior, supporting its potential as a useful measure of critical appraisal self‐efficacy.

The outstanding mechanical and chemical properties of dental enamel emerge from its complex hierarchical architecture. An accurate, detailed multiscale model of the structure and composition of enamel is important for understanding lesion formation in tooth decay (dental caries), enamel development (amelogenesis) and associated pathologies (e.g., amelogenesis imperfecta or molar hypomineralization), and minimally invasive dentistry. Although features at length scales smaller than 100 nm (individual crystallites) and greater than 50 μm (multiple rods) are well understood, competing field of view and sampling considerations have hindered exploration of mesoscale features, i.e., at the level of single enamel rods and the interrod enamel (1 to 10 μm). Here, we combine synchrotron X-ray diffraction at submicrometer resolution, analysis of crystallite orientation distribution, and unsupervised machine learning to show that crystallographic parameters differ between rod head and rod tail/interrod enamel. This variation strongly suggests that crystallites in different microarchitectural domains also differ in their composition. Thus, we use a dilute linear model to predict the concentrations of minority ions in hydroxylapatite (Mg2+ and CO₃2−/Na⁺) that plausibly explain the observed lattice parameter variations. While differences within samples are highly significant and of similar magnitude, absolute values and the sign of the effect for some crystallographic parameters show interindividual variation that warrants further investigation. By revealing additional complexity at the rod/interrod level of human enamel and leaving open the possibility of modulation across larger length scales, these results inform future investigations into mechanisms governing amelogenesis and introduce another feature to consider when modeling the mechanical and chemical performance of enamel.

Dental enamel is a complex bio-composite with compositional and structural features across a wide range of length scales. Defects in these features can compromise enamel’s ability to protect the tooth, resulting in adverse health outcomes. Acquired defects like tooth decay are familiar to most people and are the subject of numerous public health campaigns. However, developmental defects can also occur before the tooth has erupted into the mouth, which could require a lifetime of costly treatment. These congenital defects are diverse in their pathology, etiology, and prevalence, such that designing universal diagnosis and treatment protocols is challenging. Much is still not understood about the cellular and molecular mechanisms during enamel formation and how they determine properties of the final mineral; less is known about these mechanisms when they are impacted by genetic mutations or childhood illness. Clinical strategies, therefore, benefit from fundamental research of amelogenesis, the developmental process that gives rise to enamel.This thesis seeks to establish a connection between cellular processes, including those disrupted by genetic mutations, to resulting enamel structure and composition. To achieve this, a multi-scale, comprehensive combination of techniques was used to characterize mineralized dental tissues in genetically modified mouse models and in vitro organoid culture. As an integral part of this effort, a deep learning tool to process large volumes of data, which are necessary to draw conclusions about inherently varying biological systems, was developed.The presentation of topics in this thesis is as follows: First, convolutional neural networks for rapid, automatic labeling of dental tissues in μCT images of amelogenesis models are described. A demonstration of the success and limitations of semantic segmentation follows, along with a proof-of-concept analysis pipeline for extracting quantitative measurements from the labeled datasets. This tool is then used in combination with electron microscopy, vibrational spectroscopy, synchrotron μXRD mapping, histology, and immunofluorescence imaging to characterize two mouse lines modeling disruption of protein self-assembly during amelogenesis. The results indicate that mutations to different regions of protein can result in dramatically different phenotypes characterized by hypoplastic, ectopic, or hypomineralized enamel. Characterization techniques are then further applied to two efforts to expand the genetic and cellular tools available to enamel researchers. The first of these efforts is the development of novel mouse lines that allow for temporal and spatial control over genetic modifications in adult mice. The second is an in vitro model of amelogenesis generated from adult dental epithelial stem cells, which were shown to generate crystallites similar in size and composition to those in dental tissues.