Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Fracture resistance evaluation of CAD/CAM zirconia and composite primary molar crowns with different occlusal thicknesses.

OBJECTIVE: To evaluate the effect of different CAD/CAM materials and occlusal thicknesses on the fracture resistance of primary molar crowns. METHODS: Sixty extracted primary molar teeth were prepared and randomly divided into six experimental groups according to the material and thickness. Primary molar crowns with a central groove thickness of 0.3 and 0.5 mm were fabricated from CAD/CAM zirconia (group Z), zirconia-reinforced lithium silicate (group ZLS), and pre-polymerized composite resin blocks (group C). Each crown was cemented with self-adhesive resin cement on the prepared tooth. All specimens were subjected to fracture tests until fracture. Fracture load values were recorded in Newtons (N). Data were statistically analyzed using a two-way analysis of variance (ANOVA) followed by Tukey multiple comparison test. RESULTS: The highest fracture load values were obtained in group Z at 0.5 mm occlusal thickness and were significantly higher compared with the other experimental groups (p < 0.05). Although the lowest fracture load values were obtained in group ZLS at 0.3 mm occlusal thickness, all the tested CAD/CAM primary molar crowns at both thicknesses demonstrated fracture load values exceeding reported chewing force in pediatric patients. CONCLUSION: CAD/CAM primary molar crowns with reduced occlusal thickness may be used for the full-coverage restoration of primary molar teeth.

The Future of Psychotherapy in Turkey: Predictions for the Next 10 Years.

Making realistic predictions about the future is important in clinical psychology as in many other disciplines. This opinion survey aimed to examine clinical psychologists' predictions for the next 10 years regarding the status of psychotherapy in Turkey in two stages, with 107 participants in one and 69 in the other. The results revealed that the techniques predicted to increase the most in the next decade were the use of eclectic therapy, mindfulness therapy, solution-focused therapy, system/family approaches, and cognitive-behavioral therapy. Among the therapeutic interventions expected to increase in popularity were Internet-based programs, smartphone applications, and problem solving. In terms of type of psychotherapists, family counselors with certificate/graduate degrees and Internet-based treatment programs were expected to become more common, whereas it was considered that shorter treatment formats and crisis intervention approaches would be preferred. In sum, the present findings provide a current overview for Turkey and a comparison with other literature findings.

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

16-Year follow-up of an avulsed maxillary central incisor after replantation following 10-h storage: An unusual case.

Tooth avulsion is a type of dental injury defined as the complete displacement of a tooth out of the alveolar socket, and the lack of prompt treatment measures can result in the loss of function, poor quality of life, and psychological and social problems. However, several factors may not permit the immediate replantation of an avulsed tooth; therefore, delayed replantation has emerged as an alternative to meet the esthetic, functional, and psychological demands of patients. Here it was described that the successful replantation of an avulsed maxillary central incisor in a 9-year-old boy who presented at the clinic with the tooth stored in unfavorable conditions as dry and then in olive oil-milk mixture almost 10 h after the event. The tooth has remained in its socket healthy for 16 years after treatment. The patient was satisfied with both esthetics and function.

Comparative evaluation of shear bond strength of three flowable compomers on enamel of primary teeth: An in-vitro study.

BACKGROUND: The aim of the present study was to determine Shear bond strength (SBS) of different flowable compomers on the enamel surface of primary teeth. The null hypothesis to be tested was that none of the flowable compomer would differ significantly from the other two with respect to SBS. As a result, the tested materials that have the easiest application on child patient is preferred. MATERIAL AND METHODS: Sixty newly extracted non carious primary molars were selected. The buccal surface was cleaned and polished to obtain a flat enamel surface. The specimens were randomly divided into three groups of 20 teeth each, based on the flowable compomers applied, as follows: group I: Dyract Flow® (Dentsply, Konstanz, Germany); group II: Twinky Star Flow® (Voco, Cuxhaven, Germany); and group III: R&D Series Nova Compomer Flow® (Imicryl, Konya, Turkey). RESULTS: SBS in group II (6.78± 0.45 MPa) were significantly lower than groups I and III (8.30 ± 0.29 and 8.43 ± 0.66 MPa, respectively) (P<.001). No significant difference was found between groups I and III (P<.05). CONCLUSIONS: Significant differences existed between the SBS of the groups. Therefore, the null hypothesis was rejected. Flowable compomers can provide adequate SBS with self-etching system at restoration of primary teeth. Thus, successful restorations in pediatric patients can be done in a practical way. KEY WORDS: Flowable compomer, primary teeth, shear bond strength.

In vitro evaluation of microleakage of class V cavities restored with new flowable compomers on the primary teeth.

INTRODUCTION: The aim of the study was to evaluate the in vitro microleakage of new flowable compomers in the class V cavities of primary teeth. METHODS: Thirty freshly extracted, non-carious, primary molars without visible defects were used in this study. Class V cavities (n = 60), with the occlusal and cervical margins located in the enamel, were prepared on the buccal and lingual surfaces. The samples were randomly divided into 3 groups of 20 each. Group 1: restored with Twinky Star Flow (Voco, Cuxhaven, Germany), Group 2: restored with Dyract Flow (Dentsply, Konstanz, Germany) and Group 3: restored with R&D Series Nova Compomer Flow (Imicryl, Konya, Turkey) according to the manufacturer's instructions. After a thermocycling regimen of 1000 cycles between 5°C and 55°C, the samples were isolated, immersed in 0.5% basic fuchsine solution for 24 h at 37°C and sectioned longitudinally in a buccolingual direction. The sections were evaluated for values of microleakage with a stereomicroscope. RESULTS: All materials showed microleakage but no statistically significant difference was observed among the groups (p>0.05). The highest microleakage score was observed in group II (1.65 ± 0.49) and group I (1.75 ± 0.44) at occlusal and gingival margins, respectively. CONCLUSIONS: Flowable compomers showed insignificantly least amount of microleakage in class V cavities prepared on primary molars.

Effect of pulmonary surfactant on antimicrobial activity in vitro.

Time-kill curve experiments were performed with linezolid, doripenem, tigecycline, moxifloxacin, and daptomycin against Staphylococcus aureus and with colistin, moxifloxacin, and doripenem against Pseudomonas aeruginosa to evaluate the effect of porcine pulmonary surfactant on antimicrobial activity. Pulmonary surfactant significantly impaired the activities of moxifloxacin and colistin. When antibiotics are being developed for respiratory tract infections, the method described here might be used to preliminarily quantify the effect of pulmonary surfactant on antimicrobial activity.

Impact of pH on bacterial growth and activity of recent fluoroquinolones in pooled urine.

Acidification of urine is widely recommended for prevention and treatment of urinary tract infections. We set out to describe the effect of modification of pH on bacterial growth of relevant bacteria as well as on activity of modern fluoroquinolones in urine in vitro. Bacterial growth of Escherichia coli ATCC 25922 and Klebsiella oxytoca ATCC 700324 was determined in pooled human urine adjusted to pH levels between 5.0 and 8.0. Minimal inhibitory concentrations (MICs) and time-kill curves were performed for ciprofloxacin, levofloxacin and moxifloxacin in pH-adjusted urine and Mueller-Hinton Broth (MHB). Uptake of radioactive labeled [C(14)]-ciprofloxacin into bacterial cells was investigated at different pHs. While no difference in bacterial growth of E. coli and K. oxytoca was observed at pH values between 5.0 and 8.0, acidification of urine led to major impairment of antimicrobial activity of all tested fluoroquinolones, indicated by an up to 40-fold increase in MIC compared to MHB and nearly total neutralization of activity in time-kill experiments. The most probable mechanism behind this observation may have been reduced uptake of fluoroquinolones into bacterial cells, as indicated by bacterial uptake of [C(14)]-ciprofloxacin and a reversibility of the effect. The observed reduction in activity of modern fluoroquinolones confirms previous observations from older compounds.