Dual-Arch Prosthesis: Revolutionizing Partial Dentate Rehabilitation.

The utilization of natural teeth as denture abutments offers a significant advantage in retarding the residual ridge resorption (RRR). This approach distributes stress concentration between the denture-bearing areas and abutment teeth, thereby mitigating issues such as loss of sensory feedback, compromised mastication, and aesthetic concerns. Overdentures, by providing additional support and stability, play a pivotal role in reducing RRR while enhancing stability and retention. A cast partial denture (CPD) becomes the first choice in cases of long edentulous span where cross-arch stabilization is required. The simplicity of insertion, removal, and maintenance, coupled with effective oral hygiene practices, make CPDs a practical solution. This case presentation illustrates the successful prosthetic rehabilitation of a partially dentate patient through the implementation of a maxillary overdenture and mandibular CPD underscoring the efficacy of this treatment modality in achieving optimal outcomes. The combination of these prostheses restored the masticatory function, improved the aesthetics, and enhanced the quality of life of the patient. This case highlights the effectiveness of dual-arch prosthetic solutions in achieving comprehensive rehabilitation in partially dentate patients.

Ductus arteriosus diameters in fetuses with early- and late-onset fetal growth restriction.

PURPOSE: Fetal growth restriction (FGR) is a common pregnancy complication that can be associated with several adverse perinatal outcomes. One of these negative outcomes is ductus arteriosus, especially in preterm babies. In this study, intrauterine heart function and ductus diameter were evaluated in babies with FGR. METHODS: Thirty-seven fetuses with FGR were compared with 37 normal-weight fetuses at the same gestational week. In our study, ventricular diameters, aorta, pulmonary artery, ductus arteriosus (DA), aortic arch diameter, and flow traces were examined. In addition, the aorta and aortic isthmus diameters were proportioned to the ductus diameter, and the left ventricular myocardial performance index (MPI) [(ICT + IRT)/ET] was evaluated. RESULTS: There was no difference in DA diameters between the patient and control groups. The intragroup comparison of the cases with early- and late-onset FGR revealed no statistically significant difference between DA diameters. However, the ratios of the aortic annulus diameter/ductus diameter (AOD/DAD) and aortic isthmus diameter/ductus diameter (AID/DAD) were significantly lower in early-onset FGR because the diameter of the DA was greater. In addition, the mod-MPI values were higher in the patient group. CONCLUSIONS: In our study, although the ductal diameters did not change significantly in the patient group, the ductal diameter was greater in the early-onset intrauterine growth restriction (FGR) group compared with other cardiac measurements. The mod-MPI value, a cardiac function indicator, was higher in fetuses with FGR. These findings may be useful for evaluating postnatal cardiac functions in FGR.

Role of Mod(mdg4)-67.2 Protein in Interactions between Su(Hw)-Dependent Complexes and Their Recruitment to Chromatin.

Su(Hw) belongs to the class of proteins that organize chromosome architecture, determine promoter activity, and participate in formation of the boundaries/insulators between the regulatory domains. This protein contains a cluster of 12 zinc fingers of the C2H2 type, some of which are responsible for binding to the consensus site. The Su(Hw) protein forms complex with the Mod(mdg4)-67.2 and the CP190 proteins, where the last one binds to all known Drosophila insulators. To further study functioning of the Su(Hw)-dependent complexes, we used the previously described su(Hw)E8 mutation with inactive seventh zinc finger, which produces mutant protein that cannot bind to the consensus site. The present work shows that the Su(Hw)E8 protein continues to directly interact with the CP190 and Mod(mdg4)-67.2 proteins. Through interaction with Mod(mdg4)-67.2, the Su(Hw)E8 protein can be recruited into the Su(Hw)-dependent complexes formed on chromatin and enhance their insulator activity. Our results demonstrate that the Su(Hw) dependent complexes without bound DNA can be recruited to the Su(Hw) binding sites through the specific protein-protein interactions that are stabilized by Mod(mdg4)-67.2.

Magnetically modified-mitoxantrone mesoporous organosilica drugs: an emergent multimodal nanochemotherapy for breast cancer.

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

Development of a New Model System to Study Long-Distance Interactions Supported by Architectural Proteins.

Chromatin architecture is critical for the temporal and tissue-specific activation of genes that determine eukaryotic development. The functional interaction between enhancers and promoters is controlled by insulators and tethering elements that support specific long-distance interactions. However, the mechanisms of the formation and maintenance of long-range interactions between genome regulatory elements remain poorly understood, primarily due to the lack of convenient model systems. Drosophila became the first model organism in which architectural proteins that determine the activity of insulators were described. In Drosophila, one of the best-studied DNA-binding architectural proteins, Su(Hw), forms a complex with Mod(mdg4)-67.2 and CP190 proteins. Using a combination of CRISPR/Cas9 genome editing and attP-dependent integration technologies, we created a model system in which the promoters and enhancers of two reporter genes are separated by 28 kb. In this case, enhancers effectively stimulate reporter gene promoters in cis and trans only in the presence of artificial Su(Hw) binding sites (SBS), in both constructs. The expression of the mutant Su(Hw) protein, which cannot interact with CP190, and the mutation inactivating Mod(mdg4)-67.2, lead to the complete loss or significant weakening of enhancer-promoter interactions, respectively. The results indicate that the new model system effectively identifies the role of individual subunits of architectural protein complexes in forming and maintaining specific long-distance interactions in the D. melanogaster model.

Statistical considerations in model-based dose finding for binary responses under model uncertainty.

The statistical methodology for model-based dose finding under model uncertainty has attracted increasing attention in recent years. While the underlying principles are simple and easy to understand, developing and implementing an efficient approach for binary responses can be a formidable task in practice. Motivated by the statistical challenges encountered in a phase II dose finding study, we explore several key design and analysis issues related to the hybrid testing-modeling approaches for binary responses. The issues include candidate model selection and specifications, optimal design and efficient sample size allocations, and, notably, the methods for dose-response testing and estimation. Specifically, we consider a class of generalized linear models suited for the candidate set and establish D-optimal designs for these models. Additionally, we propose using permutation-based tests for dose-response testing to avoid asymptotic normality assumptions typically required for contrast-based tests. We perform trial simulations to enhance our understanding of these issues.

Comparison of six screening methods for sarcopenia among rural community-dwelling older adults: a diagnostic accuracy study.

OBJECTIVE: The objective of this analysis was to determine the diagnostic efficacy of the Ishii test, SarSA-Mod, SARC-F, SARC-Calf, SARC-F+AC, and SARC-Calf+AC for screening for sarcopenia among rural community-dwelling older adults. METHODS: The AWGS 2019 diagnostic criteria was a diagnostic reference for sarcopenia. There were six screening tools whose accuracy was determined through the use of metrics, including specificity, sensitivity, negative and positive predictive values, and the receiver operating characteristic (ROC) curve. RESULTS: The study included 551 participants (304 women, age 70.9 ± 4.9 years). The prevalence of sarcopenia was 44.5% in men and 39.1% in women. In males, the sensitivity/specificity of the Ishii test, SarSA-Mod, SARC-F, SARC-Calf, SARC-F+AC, and SARC-Calf+AC screening sarcopenia were 87.3%/65.7%, 98.2%/21.9%, 6.4%/98.5%, 28.2%/91.2%, 33.6%/83.9%, and 84.6%/43.8%, and in females, they were 68.1%/82.2, 100%/23.2%, 16.0%/90.3%, 35.3%/84.3%, 58.8%/61.1%, and 89.9%/42.2%, respectively. In males, the area under the curves of the Ishii test, SarSA-Mod, SARC-F, SARC-Calf, SARC-F+AC, and SARC-Calf+AC were 0.846 (95% CI 0.795-0.889), 0.800 (95% CI 0.745-0.848), 0.581 (95% CI 0.516-0.643), 0.706 (95% CI 0.645-0.762), 0.612 (95% CI 0.548-0.673), and 0.707 (95% CI 0.646-0.763), respectively, and in females, they were 0.824 (95% CI 0.776-0.865), 0.845 (95% CI 0.799-0.883), 0.581 (95% CI 0.524-0.637), 0.720 (95% CI 0.666-0.770), 0.632 (95% CI 0.575-0.686), and 0.715 (95% CI 0.661-0.765), respectively. CONCLUSION: Our findings demonstrate that the overall accuracy of the Ishii test was best among the six screening tools for sarcopenia screening in rural community-dwelling older adults.

PomBase: a Global Core Biodata Resource-growth, collaboration, and sustainability.

PomBase (https://www.pombase.org), the model organism database (MOD) for fission yeast, was recently awarded Global Core Biodata Resource (GCBR) status by the Global Biodata Coalition (GBC; https://globalbiodata.org/) after a rigorous selection process. In this MOD review, we present PomBase's continuing growth and improvement over the last 2 years. We describe these improvements in the context of the qualitative GCBR indicators related to scientific quality, comprehensivity, accelerating science, user stories, and collaborations with other biodata resources. This review also showcases the depth of existing connections both within the biocuration ecosystem and between PomBase and its user community.

Combination MCP-Mod for two-drug combination dose-ranging studies.

Combination therapies with multiple mechanisms of action can offer improved efficacy and/or safety profiles when compared to a single therapy with one mechanism of action. Consequently, the number of combination therapy studies have increased multi-fold, both in oncology and non-oncology indications. However, identifying the optimal doses of each drug in a combination therapy can require a large sample size and prolong study timelines, especially when full factorial designs are used. In this paper, we extend the MCP-Mod design of Bretz, Pinheiro, and Branson to a three-dimensional space to model the dose-response surface of a two-drug combination under the framework of Combination (Comb) MCP-Mod. The resulting model yields a set of dosages for each drug in the combination that elicits the target response so that an optimal dose for the combination can be selected for pivotal studies. We construct three-dimensional dose-response models for the combination and formulate the contrast test statistic to select the best model, which can then be used to select the optimal dose. Guidance to calculate power and sample size calculations are provided to assist study design. Simulation studies show that Comb MCP-Mod performs as well as the conventional multiple comparisons approach in controlling the family-wise error rate at the desired alpha level. However, Comb MCP-Mod is more powerful than the classical multiple comparisons approach in detecting dose-response relationships when treatment is non-null. The probability of correctly identifying the underlying dose-response relationship is generally higher when using Comb MCP-Mod than when using the multiple comparisons approach.

Influence of internal angle and shape of the lining on residual stress of Class II molar restorations.

Polymerization shrinkage is a major side effect of resin composite materials that affects the success and longevity of caries restorations. This study was to analyze the effect of the internal angle and shape of the lining on the shrinkage residual stress of dental restorations in Class II mesio-occlusal-distal (MOD) cavities through finite element analysis (FEA). A 3D reconstructed model of a human mandibular first molar was created from micro-CT images, and then the tooth was prepared as a Class II MOD cavity. 3D models of four regular internal corner shapes of Class II MOD cavities with different internal angles of lining and one 90° filleted corner model were created. The thermal expansion technique was applied to approximate the shrinkage impact of composite resin polymerization in the FE software ABAQUS. Von Mises stress was taken as a metric. The results showed that the level of residual stresses in the Class II MOD cavities was greatly dependent on the internal angle of the lining. The maximum von Mises stress in tooth tissue decreased as the internal angle of the lining increased. The internal shapes of the lining had no obvious effect on the stress, and the filleted corner model had less stress. This lining strategy is appropriate for Class II MOD cavities with serious loss of tooth tissue.

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer.

INTRODUCTION: Joint linkage and association (JLA) analysis combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. METHODS: In this paper, we present an extension to the GENEHUNTER-MODSCORE software package that enables a JLA analysis based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. Our new JLA method is an extension of the MOD score approach for linkage analysis, which allows the estimation of trait-model and linkage disequilibrium (LD) parameters, i.e., penetrance, disease-allele frequency, and haplotype frequencies. LD is modeled between alleles at a single diallelic disease locus and up to three diallelic test markers. Linkage information is contributed by additional multi-allelic flanking markers. We investigated the statistical properties of our JLA implementation using extensive simulations, and we compared our approach to another commonly used single-marker JLA test. To demonstrate the applicability of our new method in practice, we analyzed pedigree data from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). RESULTS: Based on the simulated data, we demonstrated the validity of our JLA-MOD score analysis implementation and identified scenarios in which haplotype-based tests outperformed the single-marker test. The estimated trait-model and LD parameters were in good accordance with the simulated values. Our method outperformed another commonly used JLA single-marker test when the LD pattern was complex. The exploratory analysis of the FaPaCa families led to the identification of a promising genetic region on chromosome 22q13.33, which can serve as a starting point for future mutation analysis and molecular research in pancreatic cancer. CONCLUSION: Our newly proposed JLA-MOD score method proves to be a valuable gene mapping and characterization tool, especially when either linkage or association information alone provide insufficient power to identify the disease-causing genetic variants.

Fracture resistance and failure pattern of endodontically treated maxillary premolars restored with transfixed glass fiber post: an in vitro and finite element analysis.

The aims of the study were to determine the effect of different types of endodontic sealers and the presence of a horizontal glass fiber post (HGFP) on the fracture resistance and fracture pattern of mesio-occluso-distal (MOD) restored upper premolars and to analyze the stress distribution. Sixty extracted upper premolars received root canal treatment (RCT) and a MOD cavity preparation. All MOD cavities were restored with the same composite resin (CR). The 60 teeth were divided randomly into 6 groups (n = 10); Group1= AH Plus sealer; Group 2= TotalFill BC sealer; Group 3= BioRoot RCS sealer; Group 4= AH plus sealer + HGFP; Group 5= TotalFill BC sealer + HGFP; and, Group 6= Bio Root RCS sealer + HGFP. All specimens were thermocycled and subjected to cyclic loading. Next, the specimens were subjected to a static load using a universal testing machine. Data were analyzed using two-way ANOVA. Two micro-CTs of the same upper premolar, one without the HGFP and later one with HGFP inserted were made and used to create two finite element (FE) models. For the fracture resistance, two-way ANOVA revealed significant differences for the effect of HGFP (p = 0.029), but no differences for the effect of root canal sealer type (p = 0.561). The HGFP groups showed higher restorable fracture compared to groups without HGFP (p = 0.013). Finite element analysis showed that the inclusion of HGFP reduces stress concentration at the occlusal interface and cervical region. Therefore, it can be concluded that HGFP significantly increased the fracture resistance of endodontically treated upper premolars with MOD cavities and reduced the risk for non-restorable fractures. The FE analysis supports the mechanical test results.

Reference Ranges for Left Modified Myocardial Performance Index: Systematic Review and Meta-Analysis.

INTRODUCTION: The modified myocardial performance index (mod-MPI) is a noninvasive Doppler-derived metric used to evaluate fetal cardiac function. However, the reference ranges for mod-MPI in normal fetuses are not clearly defined, which limits the use of this technology in fetuses with potential cardiac compromise. Thus, we aimed to perform a systematic review and meta-analysis of published mod-MPI reference ranges across gestation. METHODS: The published literature was systematically searched, and all published articles in any language that provided values for the left ventricular mod-MPI obtained in low-risk, singleton fetuses were considered eligible for further review. All retrieved titles and abstracts were independently reviewed by two researchers. Mean and standard deviation by gestational week was extracted or calculated from published data. DerSimonian-Laird random-effects models were used to estimate pooled means and 95% confidence intervals (CIs). RESULTS: The search resulted in 618 unique citations, of which 583 did not meet inclusion criteria, leaving 35 abstracts selected for full-text review. Review of the references of these 35 articles identified another 5 studies of interest. Of the 40 articles reviewed, six met inclusion criteria. There was significant heterogeneity seen in the mod-MPI results reported. Mod-MPI increased as pregnancy progressed in all studies. The pooled mean mod-MPI at 11 weeks' gestation was 0.400 (95% CI 0.374-0.426) and increased to 0.585 (95% CI 0.533-0.637) at 41 weeks' gestation. The increase was linear in 5 of 6 studies, while in 1 study, the mod-MPI was stable until 27 weeks' gestation, and then increased throughout the third trimester. Despite all having trends increasing over pregnancy, there was no study in which all the weekly means fell within the pooled 95% CI. CONCLUSION: While mod-MPI does increase over gestation, the true "reference ranges" for fetuses remain elusive. Future efforts to further optimize calculation of time intervals possibly via automation are desperately needed to allow for reproducibility of this potentially very useful tool to assess fetal cardiac function.

Static mechanical analysis of the vertebral body after modified anterior cervical discectomy and fusion (partial vertebral osteotomy): a finite element model.

BACKGROUND: Modified anterior cervical discectomy and fusion (Mod ACDF) can effectively address ossification of the posterior longitudinal ligament (OPLL), which is difficult to remove directly from the posterior edge of the vertebral body, with considerably lesser damage as compared to anterior cervical corpectomy and fusion (ACCF). We compared the static mechanics of different anterior approaches by using an ideal finite element model. METHODS: A complete finite element model was established and classified into the following three surgical models according to different model cutting operations: ACDF, ACCF, and Mod ACDF. Three different bone volume situations (normal bone mineral density, osteopenia, and osteoporosis) were simulated. After fixing the lower surface of C5 or C6, a load was applied to the upper surface of C4, and the stress distribution and displacement of the upper surface of C5 or C6 were observed and the related values were recorded. RESULTS: The average Von Mises Stress and displacement levels of Mod ACDF were between those of ACDF and ACCF; with the peak Von Mises Stress occurring on the posterior side of the vertebral body (Points 1-4). The change in Von Mises Stress of the vertebral body is not significant during bone loss. However, the degree of displacement of the vertebral body surface and risk of vertebral collapse are increased (100 N: 13.91 vs. 19.47 vs. 21.62 µm; 150 N: 19.60 vs. 29.30 vs. 31.64 µm; 200 N: 28.53 vs. 38.65 vs. 44.83 µm). CONCLUSIONS: The static biomechanical effects caused by Mod ACDF are intermediate between ACDF and ACCF, and the risk of vertebral body collapse is lower than that by ACCF. Therefore, Mod ACDF may be an effective solution when targeting OPLL with poorly positioned posterior vertebral body edges.

Calculation of Phase 2 dose-finding study sample size for reliable Phase 3 dose selection.

Sample sizes of Phase 2 dose-finding studies, usually determined based on a power requirement to detect a significant dose-response relationship, will generally not provide adequate precision for Phase 3 target dose selection. We propose to calculate the sample size of a dose-finding study based on the probability of successfully identifying the target dose within an acceptable range (e.g., 80%-120% of the target) using the multiple comparison and modeling procedure (MCP-Mod). With the proposed approach, different design options for the Phase 2 dose-finding study can also be compared. Due to inherent uncertainty around an assumed true dose-response relationship, sensitivity analyses to assess the robustness of the sample size calculations to deviations from modeling assumptions are recommended. Planning for a hypothetical Phase 2 dose-finding study is used to illustrate the main points. Codes for the proposed approach is available at https://github.com/happysundae/posMCPMod.

Evaluation of fracture behavior in short fiber-reinforced direct and indirect overlay restorations.

OBJECTIVES: The aim was to assess how incorporating a short-fiber composite (SFC) core would affect the fracture behavior of direct and indirect overlays. Furthermore, to examine the relationship between the thickness ratio of SFC core to particulate-filled composite (PFC) veneering and the fracture-behavior of bilayered-structured restorations. MATERIALS AND METHODS: A total of 120 molars were used to create MOD cavities, with palatal cusps removed. Four different groups of direct overlays were then made (n = 15/group), all of which featured a SFC core (everX Flow) with varying thicknesses (0, 1, 4, and 5 mm), as well as a surface layer of PFC (G-aenial Posterior), with the overall thickness of the bilayered-structured restoration set at 5 mm. Additionally, four groups of CAD/CAM restorations were created (Cerasmart 270 and Initial LiSi Block), with or without 2 mm of SFC core reinforcement. Following the fabrication of these restorations, cyclic fatigue aging was carried out for a total of 500,000 cycles, with an applied maximum load (Fmax) of 150 N. Subsequently, each restoration underwent quasi-static loading until fracture. The fracture mode was subsequently evaluated using optical microscopy and SEM. RESULTS: There were no statistically significant differences (p > 0.05) observed in the fracture resistance of indirect overlays reinforced with a 2-mm SFC core compared to those made solely from restorative materials. Direct overlays constructed using plain SFC or with a 4-mm layer thickness of SFC core exhibited significantly higher fracture resistance values (2674 ± 465 and 2537 ± 561 N) (p < 0.05) when compared to all other groups tested, according to the statistical analysis ANOVA. CONCLUSIONS: The most effective method for restoring large MOD cavities was found to be direct restoration using SFC either alone or as a bulk core in combination with PFC composite. CLINICAL RELEVANCE: The use of SFC as bulk reinforcing base will significantly improve the loading performance of directly layered restorations.

Polygenic scores of diabetes-related traits in subgroups of type 2 diabetes in India: a cohort study.

Background: A machine-learning approach identified five subgroups of diabetes in Europeans which included severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) with partially distinct genetic aetiologies. We previously validated four of the non-autoimmune subgroups in people with young-onset type 2 diabetes (T2D) from the Indian WellGen study. Here, we aimed to apply European-derived centroids and genetic risk scores (GRSs) to the unselected (for age) WellGen to test their applicability and investigate the genetic aetiology of the Indian T2D subgroups. Methods: We applied European derived centroids and GRSs to T2D participants of Indian ancestry (WellGen, n = 2217, 821 genotyped) and compared them with normal glucose tolerant controls (Pune Maternal Nutrition Study, n = 461). Findings: SIDD was the predominant subgroup followed by MOD, whereas SIRD and MARD were less frequent. Weighted-GRS for T2D, obesity and lipid-related traits associated with T2D. We replicated some of the previous associations of GRS for T2D, insulin secretion, and BMI with SIDD and MOD. Unique to Indian subgroups was the association of GRS for (a) proinsulin with MOD and MARD, (b) liver-lipids with SIDD, SIRD and MOD, and (c) opposite effect of beta-cell GRS with SIDD and MARD, obesity GRS with MARD compared to Europeans. Genetic variants of fucosyltransferases were associated with T2D and MOD in Indians but not Europeans. Interpretation: The similarities emphasise the applicability of some of the European-derived GRSs to T2D and its subgroups in India while the differences highlight the need for large-scale studies to identify aetiologies in diverse ancestries. The data provide robust evidence for genetically distinct aetiologies for the T2D subgroups and at least partly mirror those seen in Europeans. Funding: Vetenskapsrådet, Diabetes Wellness, and Hjärt-Lungfonden (Sweden), DST (India), Wellcome Trust, Crafoord Foundation and Albert Påhlsson Foundation.

Modified nucleic acid aptamers: development, characterization, and biological applications.

Aptamers are single-stranded oligonucleotides that bind to their targets via specific structural interactions. To improve the properties and performance of aptamers, modified nucleotides are incorporated during or after a selection process such as systematic evolution of ligands by exponential enrichment (SELEX). We summarize the latest modified nucleotides and strategies used in modified (mod)-SELEX and post-SELEX to develop modified aptamers, highlight the methods used to characterize aptamer-target interactions, and present recent progress in modified aptamers that recognize different targets. We discuss the challenges and perspectives in further advancing the methodologies and toolsets to accelerate the discovery of modified aptamers, improve the throughput of aptamer-target characterization, and expand the functional diversity and complexity of modified aptamers.

Improved inference for MCP-Mod approach using time-to-event endpoints with small sample sizes.

The Multiple Comparison Procedures with Modeling Techniques (MCP-Mod) framework has been recently approved by the U.S. Food, Administration, and European Medicines Agency as fit-for-purpose for phase II studies. Nonetheless, this approach relies on the asymptotic properties of Maximum Likelihood (ML) estimators, which might not be reasonable for small sample sizes. In this paper, we derived improved ML estimators and correction for their covariance matrices in the censored Weibull regression model based on the corrective and preventive approaches. We performed two simulation studies to evaluate ML and improved ML estimators with their covariance matrices in (i) a regression framework (ii) the Multiple Comparison Procedures with Modeling Techniques framework. We have shown that improved ML estimators are less biased than ML estimators yielding Wald-type statistics that controls type I error without loss of power in both frameworks. Therefore, we recommend the use of improved ML estimators in the MCP-Mod approach to control type I error at nominal value for sample sizes ranging from 5 to 25 subjects per dose.

On the fracture behavior of molar teeth with MOD cavity preparation.

Mesial-occlusal-distal (MOD) cavity preparations are commonly used to restore damaged teeth. While numerous in vitro cavity designs have been devised and tested, no analytical frameworks for assessing their resistance to fracture seem to exist. This concern is addressed here by resorting to a 2D slice specimen cut from restored molar teeth with rectangular-base MOD cavity. The evolution of damage due to axial cylindrical indentation is followed in situ. The failure begins with a rapid debonding along the tooth/filler interface and continues with unstable cracking from the cavity corner. The debonding load qd is fairly fixed while the failure load qf is insensitive to the presence of filler, increasing with cavity wall thickness h and reducing with cavity depth D. The growth of the corner crack is studied using a 2D fracture analysis in conjunction with the FEM technique. The ratio h = h/D emerges as a viable system parameter. A simple expression for qf given in terms of h and dentin toughness KC is developed that predicts well the test data. In vitro studies on full-fledged molar teeth with MOD cavity preparation show that the fracture resistance of filled cavities often exceeds by a large margin that of unfilled ones. Indications are that this may reflect load sharing with the filler. Thus, the fracture resistance of the unfilled cavity provides a lower bound to a compromised MOD filling after long-term aging in the mouth. This bound is well predicted by the slice model. Finally, it is recommended that MOD cavities be prepared, if applicable, such that h > D regardless of the tooth size.