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Numerical modeling offers a valuable alternative to analytical solutions for pumping test analysis. However, little is known about how discretization impacts results accuracy and runtime. This study presents a systematic method for defining the spatiotemporal discretization of pumping test numerical models based on dimensionless parameters. Two types of analysis are considered: one where observations are made in the pumping well, and another one where observations are made in different wells. The influence of the discretization parameters on results accuracy and runtime is investigated and an optimal set of parameters is determined that minimizes runtime while maintaining the maximum error under 1% for an "average" aquifer. Lower runtimes are achieved when the analysis focuses on the pumping well, which is attributed to the steady-state analytical solution approximating drawdown in the well in the numerical scheme employed. Additional tests demonstrate the robustness of the derived set of parameters in different configurations., (© 2024 National Ground Water Association.)

Objective: Microvascular decompression (MVD) in trigeminal neuralgia (TN) is currently managed using an operating microscope (OM). Recent experiences with endoscopy-assisted, fully endoscopic, and exoscopic surgery have been described, aiming to improve ergonomics and image quality. The aim of this study was to report the first series of patients operated on with the aid of a robotic binocular exoscope using a head-mounted display (RoboticScope)., Methods: From September 2023 to March 2024, 9 patients with TN were treated using the RoboticScope. A classic mini-retrosigmoid approach was performed and standard microsurgical techniques were applied. Surgical timing, ergonomics, visual performances, adverse events, and 1-month postoperative pain outcomes were evaluated., Results: All surgeries were completed without shifting to the OM. Surgeon comfort with the RoboticScope was better compared with the OM and visualization was good. No intraoperative adverse events were recorded. The duration of the procedure was significantly shorter with the RoboticScope compared to those using the OM (median 18 vs 34 minutes, p = 0.0001)., Conclusions: MVD can be safely and effectively performed using the RoboticScope. Surgeons benefit from better ergonomics, stereoscopic image quality, and shorter surgical duration.

Background: The management of endodontic infections is a complex challenge, mainly due to the involvement of diverse microorganisms and their by-products. This study aimed to evaluate the efficacy of N-acetylcysteine (NAC), calcium hydroxide (Ca(OH) 2 ), and their combined application as intracanal medications in combating Enterococcus faecalis , Escherichia coli , and lipopolysaccharides (LPS) from E. coli ., Methods: A total of 60 single-rooted human teeth were carefully selected and divided into six groups. These tooth canals were deliberately exposed to E. faecalis (ATCC 29212) and E. coli (ATCC 25922) to induce biofilm formation. Subsequently, the specimens were treated with NAC, Ca(OH) 2 , or a combination of both substances. Three samples of the root canals were collected at three moments: the first sample (S1) was to confirm the initial contamination, the second sample (S2) was immediately post-instrumentation, and the third sample (S3) was collected after the use of the intracanal medication. The antimicrobial efficacy of these intracanal medications was assessed by enumerating colony-forming units per milliliter (CFU/mL). In addition to this, the kinetic chromogenic Limulus Amebocyte Lysate (LAL) assay by Lonza was used to quantify LPS from E. coli . Data tested for normality; then, Kruskal-Wallis and Friedman tests were used, and Dunn's for multiple comparisons., Results: The findings of this study showed significant reductions in the microbial load of E. faecalis and E. coli by S3. Notably, there were no statistically significant differences among the treatment groups concerning these microorganisms. However, it was observed that only the combination of NAC and Ca(OH) 2 led to a noteworthy decrease in the quantity of E. coli's LPS after 7-days, demonstrating a statistically significant difference from the other treatment groups. NAC + Ca(OH) 2 combination, applied for a duration of 7-days, proved to be more suitable in reducing the presence of E. faecalis , E. coli , and LPS from E. coli within the context of endodontic infections., Competing Interests: Amjad Abu Hasna is an Academic Editor for PeerJ., (© 2024 Khoury et al.)

The objective of the present case report is to describe Icon resin infiltration as a treatment option for postorthodontic white spot lesions (WSLs). A 23-year-old male patient complained of white spots on his maxillary anterior teeth that caused him significant esthetic concern in terms of his smile and affected his self-esteem. During the anamnesis, the patient reported that he noticed white spots directly after the brackets were removed after orthodontic treatment, which had not yet been completed. Based on the information obtained through the anamnesis and the clinical examination, the spots were deemed to be remineralized WSLs. The proposed treatment consisted of supervised at-home tooth whitening through bleaching in combination with microabrasion and resin infiltration. The clinical results were successful, showing significant improvement in terms of esthetics and the patient's self-esteem after only a single session of resin infiltration with Icon material. Treatment optimization and gain in clinical time were clearly demonstrated as well as the preservation of tooth tissue compared with other treatments.

Surgery and endovascular therapy are the primary treatment options for spinal dural arteriovenous fistula (SDAVF). Due to the absence of a consensus regarding which therapy yields a superior outcome, we conducted a comparative analysis of the surgical and endovascular treatment of SDAVF through a multicenter case series and a systematic literature review. Patients with SDAVF, surgically or endovascularly treated at four neurosurgical centers from January 2001 to December 2021, were included in this study. Level of SDAVF, primary treatment modality, baseline and post-procedural neurological status were collected. The primary outcomes were failure, complication rates, and a newly introduced parameter named as therapeutic delay. A systematic review of the literature was performed according to PRISMA-P guidelines. The systematic review identified 511 papers, of which 18 were eligible for analysis, for a total of 814 patients, predominantly male (72%) with a median age of 61 and mainly thoracic SDAVFs (65%). The failure rate was significantly higher for endovascular therapy (20%) compared to surgery (4%) (p < 0.01). Neurological complications were generally rare, with similar rates among the two groups (endovascular 2.9%; surgery 2.6%). Endovascular treatment showed a statistically significantly higher rate of persistent neurological complications than surgical treatment (2.9% versus 0.2%; p < 0.01). Both treatments showed similar rates of clinical improvement based on Aminoff Logue scale score. The multicenter, retrospective study involved 131 patients. The thoracic region was the most frequent location (58%), followed by lumbar (37%). Paraparesis (45%) and back pain (41%) were the most common presenting symptoms, followed by bladder dysfunction (34%) and sensory disturbances (21%). The mean clinical follow-up was 21 months, with all patients followed for at least 12 months. No statistically significant differences were found in demographic and clinical data, lesion characteristics, or outcomes between the two treatment groups. Median pre-treatment Aminoff-Logue score was 2.6, decreasing to 1.4 post-treatment with both treatments. The mean therapeutic delay for surgery and endovascular treatment showed no statistically significant difference. Surgical treatment demonstrated significantly lower failure rates (5% vs. 46%, p < 0.01). In the surgical group, 2 transient neurological (1 epidural hematoma, 1 CSF leak) and 3 non-neurological (3 wound infections) complications were recorded; while 2 permanent neurological (spinal infarcts), and 5 non-neurological (inguinal hematomas) were reported in the endovascular group. According to the literature review and this multicenter clinical series, surgical treatment has a significantly lower failure rate than endovascular treatment. Although the two treatments have similar complication rates, endovascular treatment seems to have a higher rate of persistent neurological complications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This laboratory study evaluated the effect of three polishing systems on the surface roughness and gloss of resin composites., Materials and Methods: Thirty specimens (6 mm Ø × 8 mm) were fabricated from each of three resin composites: Z 350 XT (nanofill), Harmonize (nanohybrid), and Estelite Omega (supranonofill). All specimens were photopolymerized using a multi-peak LED curing unit (VALO-Standard mode), having a exitance irradiance of approximately 1000 mW/cm 2 against a polyester strip (PS). 2 mm was then removed from the irradiated end (finished) using #320 abrasive paper (F). Specimens were then randomly polished (P) using a one-step (1S) (OneGloss), two-step (2S) (EVE Diacomp Twist Basic CA), or 3-step (3S) (Astropol P) system (n = 10). For PS, F, and P groups, surface roughness (Ra) was measured using a surface roughness tester, and surface gloss was measured with a glossmeter. For each specimen, the percent recovery to the PS value (%R) of surface roughness and surface gloss were calculated. Data were analyzed using two-way ANOVA, followed by Tukey's test. Surface roughness and gloss values were submitted to Pearson's correlation test (α = 0.05). All statistical testing was performed using a pre-set alpha of 0.05., Results: The interaction term [resin composite × polishing system] was significant for both surface roughness (p = 0.001) and gloss (p = 0.0001). For all resin composites, the 2S and 3S systems provided a higher %R of surface roughness and gloss compared to those of the 1S system. There was a negative correlation between surface roughness and gloss, but only a few combinations showed strong correlations., Conclusions: The 2S and 3S polishing systems provided surfaces having greater smoothness and gloss compared to the 1S system. The ability to recover surface roughness and gloss was dependent on type of resin composite filler classification., Clinical Significance: The 3S and 2S polishing systems were more effective in achieving PS values than was the 1S system for all tested resin composites. However, individual polishing systems performed differently depending on type of resin composite., (© 2023 Wiley Periodicals LLC.)

Objectives: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects., Methods: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann-Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores., Results: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores., Conclusions: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects., (© 2023 British HIV Association.)

Introduction: This systematic review examined the effect of neutralizing agents on bond strength after irrigation with sodium hypochlorite and their existing protocols in literature., Methods: This present study adhered to the PRISMA guidelines and was registered at PROSPERO. Five electronic databases were searched (sept-2020/jan-2021) in English, Spanish, and Portuguese, without any restrictions on publication date. Cases reports, editorials and literature reviews were not included. The risk of bias was assessed using the Cochrane Collaboration tool. From the initial 7,147 studies, 2,745 were removed as duplicates and 4,382 were excluded after a title/abstract screen., Results: Seventeen in vitro studies were included. The results showed that the higher the concentration of sodium hypochlorite, the lower the bond strength at dentine/restoration interface (p⟨0.01). Among the studies, sodium ascorbate was the most widely used neutralizer and showed the most significant results in increasing bond strength (p⟨0.01). The bond strength values were found to increase with longer application time of the neutralizing substances (p⟨0.01)., Conclusions: The use of sodium ascorbate as a neutralizing agent can reverse the negative effects of the sodium hypochlorite and improve the bond strength between dentine and resin cement, however, it isn't possible to determine the best protocol for use., (Copyright© 2024 Dennis Barber Ltd.)

Abstract: Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematologic malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematologic malignancy, somatic mutations were detected in at least 1 of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP- or AML-driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in ≥2 patients without hematologic malignancy. Moreover, 3 unrelated patients (1 with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in older adult patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. This trial was registered at www.clinicaltrials.gov as #NCT03854318., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The awareness of molar incisor hypomineralisation (MIH) has led to its increased clinical detection, consequently drawing more attention to its associated complications. This text offers an overview of the esthetic management of anterior teeth affected by MIH, a condition characterized by enamel defects that present significant cosmetic challenges. The focus is on the clinical presentation of MIH characteristics, considering the depth of lesions and the clinical aspects, and the treatment protocols available, despite a lack of extensive scientific evidence. To the best of the current scientific knowledge, the text evaluates the potential of minimally invasive procedures, as well as the use of traditional composite resin techniques and their possible combinations, highlighting the critical role of esthetic considerations for the impacted anterior teeth. The chapter is augmented with five illustrative clinical cases that display the practical application of these treatment approaches. These examples articulate the clinical decision-making process and personalized restorative strategies, aiming to balance function with enhanced esthetic results. The described cases act as a roadmap for clinicians tackling the complexities of MIH treatment in the context of limited empirical evidence, providing insights into achieving both satisfactory and esthetically pleasing outcomes for patients suffering from this condition., (© 2024 S. Karger AG, Basel.)

Objectives: To answer the following research question: does the clinical evaluation of restorations on permanent teeth with bioactive materials show greater retention rates than those with non-bioactive materials?, Materials and Methods: A search strategy was used in the following databases: MEDLINE via PubMed, Scopus, Web of Science, LILACS, BBO, Embase, The Cochrane Library, and OpenGrey. Randomized controlled trials (RCTs), with a minimum of 2-year follow-up and evaluating at least one bioactive material in permanent teeth were included. Risk of bias was detected according to the Cochrane Collaboration tool for assessing the risk of bias (RoB 2.0), and network meta-analysis was performed using a random-effects Bayesian-mixed treatment comparison model., Results: Twenty-seven studies were included. The success of the restorations was assessed using modified USPHS system in 24 studies and the FDI criteria in 3 studies. Network meta-analysis revealed three networks based on restoration preparations. Resin composites were ranked with higher SUCRA values, indicating a greater likelihood of being the preferred treatment for class I, II, and III restorations. In class V, resin-modified glass ionomer cement was ranked with the highest value., Conclusion: Bioactive restorative materials showed similar good clinical performance in terms of retention similarly to conventional resin composites., Clinical Significance: The findings must be interpreted with caution because many RCT on restorative materials aim to verify the equivalence of new materials over the gold standard material rather than their superiority. The present systematic review also suggests that new RCT with longer follow-up periods are necessary., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

The study investigated the ability of bioactive materials used to restore enamel and dentine specimens to prevent caries. Enamel (n = 50) and dentine (n = 50) specimens were obtained from bovine incisors, prepared, and randomly allocated to one of five groups according to the restorative treatment: alkasite without adhesive system; alkasite with adhesive system; high viscosity glass ionomer cement; resin composite; no restoration; negative control group. Specimens were restored, exposed to a thermal cycling aging protocol, sterilized, and exposed to a cariogenic challenge induced by Streptococcus mutans and then submitted to surface and subsurface microhardness tests and polarized light microscopy to verify the caries lesion development in enamel or dentine surrounding the restorative materials. Data were analyzed using one-way ANOVA. In enamel and dentine, glass ionomer cement, alkasite without and with adhesive system presented a lower percentage surface microhardness loss than resin composite and negative control. Enamel subsurface microhardness presented no statistically significant differences between glass ionomer cement, alkasite without and with adhesive system. Glass ionomer cement also did not present statistically significant differences from resin composite and the negative control. In dentine, glass ionomer cement showed the highest subsurface microhardness values. In conclusion, bioactive restorative materials provide greater protection to enamel and dentine against surface caries development than resin composite., (© 2023 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

The current view of hematopoiesis considers leukocytes on a continuum with distinct developmental origins, and which exert non-overlapping functions. However, there is less known about the function and phenotype of ontogenetically distinct neutrophil populations. In this work, using a photoconvertible transgenic zebrafish line; Tg(mpx:Dendra2), we selectively label rostral blood island-derived and caudal hematopoietic tissue-derived neutrophils in vivo during steady state or upon injury. By comparing the migratory properties and single-cell expression profiles of both neutrophil populations at steady state we show that rostral neutrophils show higher csf3b expression and migration capacity than caudal neutrophils. Upon injury, both populations share a core transcriptional profile as well as subset-specific transcriptional signatures. Accordingly, both rostral and caudal neutrophils are recruited to the wound independently of their distance to the injury. While rostral neutrophils respond uniformly, caudal neutrophils respond heterogeneously. Collectively, our results reveal that co-existing neutrophils populations with ontogenically distinct origin display functional differences., (© 2023. Springer Nature Limited.)

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like receptor 4 (TLR4) and type I interferon (IFN) signaling. RUNX1 loss in GMPs augments neutrophils' inflammatory response to the TLR4 ligand lipopolysaccharide through increased expression of the TLR4 coreceptor CD14. RUNX1 binds Cd14 and other genes encoding proteins in the TLR4 and type I IFN signaling pathways whose chromatin accessibility increases when RUNX1 is deleted. Transcription factor footprints for the effectors of type I IFN signaling-the signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRFs)-were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT1::STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons that were derepressed in RUNX1-deficient GMPs and neutrophils. We conclude that a major direct effect of RUNX1 loss in GMPs is the derepression of type I IFN and TLR4 signaling, resulting in a state of fixed maladaptive innate immunity., (© 2023 Zezulin et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: This study aimed to compare a connective tissue graft (CTG) to a (porcine) xenogeneic acellular dermal matrix (XDM), both associated with modified coronally advanced flap (MCAF) and partial resin composite restoration to treat multiple combined defects (CDs)., Methods: Seventy-eight defects in 38 patients presenting multiple combined defects, that is, gingival recession associated with non-carious cervical lesions, were treated by partial resin composite restoration (apical margin up to 1 mm of the estimated cement-enamel junction) and MCAF along with CTG or XDM. After 6 months, the groups were compared with regard to clinical, patient-centered, and esthetic outcomes., Results: CD coverage was 72.9% for CTG versus 50.7% for XDM (P < 0.001). Recession reduction was 2.3 mm for CTG versus 1.5 mm for XDM (P < 0.001). CTG resulted in a greater increase in keratinized tissue width (CTG: 0.96 mm vs. XDM: 0.3 mm, P = 0.04) and gingival thickness (CTG: 0.9 mm vs. XDM: 0.3 mm, P < 0.001). Both treatments successfully reduced dentin hypersensitivity and increased esthetics satisfaction, with no statistically significant intergroup differences. Moreover, XDM patients experienced a shorter surgery duration (CTG: 57.2 min vs. XDM: 37.4 min, P < 0.001) and less time to no pain (visual analog scale  =  0; CTG: 6.5 days vs. XDM: 3.5 days, P = 0.04)., Conclusion: CTG resulted in significantly greater root coverage and increased keratinized tissue width compared to XDM for treating multiple partially restored CDs. However, increased root coverage at the CTG sites was accounted for by increased probing depth compared to the XDM sites., (© 2023 American Academy of Periodontology.)

Objective: The aim of this double-blind, randomized trial was to evaluate the influence of the occlusogingival distance (OGD) in noncarious cervical lesions (NCCLs) on the clinical performance of a regular bulk-fill resin composite and a regular nanofilled resin composite., Materials and Methods: One hundred and forty NCCLs in 77 participants were randomly divided into four groups (n = 35), according to OGD (1.5 mm ± 10% or 3 mm ± 10%) and resin composites (Filtek Bulk Fill Posterior [B] or Filtek Z350 XT [C]), namely: 1.5 mm-B, 1.5 mm-C, 3 mm-B, and 3 mm-C. The restorations were bonded using a two-step self-etch adhesive (Clearfil SE Bond), applied following the manufacturer's instructions. Restorations were polished 1 week after placement. Two experienced and calibrated examiners evaluated the restorations using modified US Public Health Service criteria at baseline (7 days) and after 6, 12, 18, 24, and 30 months. Statistical analyses were carried out using Kruskal-Wallis, Friedman's repeated measures analysis of variance, and the Wilcoxon signed rank test (α = 0.05)., Results: After 30 months, the recall rate was 94.2%. Eight restorations were lost (3 for 1.5 mm-C, 2 for 1.5 mm-B, 1 for 3 mm-C, and 2 for 3 mm-B). All groups resulted in a significantly worse marginal discoloration and surface texture at 30 months in comparison with the baseline (1 week). No significant difference was found for the other parameters., Conclusion: The restorations performed with both resin composites produced clinically acceptable restorations. The OGD of NCCLs did not influence the clinical performance of restorations., Clinical Significance: The OGD of NCCLs did not have a significant effect on the clinical performance of a regular bulk-fill and nanofilled restorations. Both materials showed a very good performance on 30-month evaluation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Growth hormone secretagogues (GHSs) exert multiple actions, being able to activate GHS-receptor 1a, control inflammation and metabolism, to enhance GH/insulin-like growth factor-1 (IGF-1)-mediated myogenesis, and to inhibit angiotensin-converting enzyme. These mechanisms are of interest for potentially targeting multiple steps of pathogenic cascade in Duchenne muscular dystrophy (DMD)., Methods: Here, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, via a multidisciplinary in vivo and ex vivo comparison in mdx mice, of two ad hoc synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mdx mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.)., Results: In vivo , both GHSs increased mice forelimb force (recovery score, RS towards WT: 20% for EP80317 and 32% for JMV2894 at week 8). In parallel, GHSs also reduced diaphragm (DIA) and gastrocnemius (GC) ultrasound echodensity, a fibrosis-related parameter (RS: ranging between 26% and 75%). Ex vivo , both drugs ameliorated DIA isometric force and calcium-related indices ( e.g. , RS: 40% for tetanic force). Histological analysis highlighted a relevant reduction of fibrosis in GC and DIA muscles of treated mice, paralleled by a decrease in gene expression of TGF-β1 and Col1a1 . Also, decreased levels of pro-inflammatory genes ( IL-6, CD68 ), accompanied by an increment in Sirt-1, PGC-1α and MEF2c expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of GHS receptor-1a , nor an increase of circulating IGF-1 were found, suggesting the presence of a novel receptor-independent mechanism in skeletal muscle. Preliminary docking studies revealed a potential binding capability of JMV2894 on metalloproteases involved in extracellular matrix remodeling and cytokine production, such as ADAMTS-5 and MMP-9, overactivated in DMD., Discussion: Our results support the interest of GHSs as modulators of pathology progression in mdx mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boccanegra, Cappellari, Mantuano, Trisciuzzi, Mele, Tulimiero, De Bellis, Cirmi, Sanarica, Cerchiara, Conte, Meanti, Rizzi, Bresciani, Denoyelle, Fehrentz, Cruciani, Nicolotti, Liantonio, Torsello and De Luca.)

Objective: To compare 2 different resin composites and 2 adhesive systems used in a new restorative protocol (partial restoration) to treat non-carious cervical lesions associated with gingival recession type 1 (RT1)., Material and Methods: Eighty combined defects (CDs) were treated with a partial restoration and periodontal plastic surgery for root coverage. The CDs were randomly assigned to one of the following groups: NP + TE (n = 20), nanofilled composite and 2-step total-etch adhesive system; NP + UA (n = 20), nanofilled composite and universal adhesive system; MH + TE (n = 20), microhybrid composite and 2-step total-etch adhesive; MH + UA (n = 20), microhybrid composite and universal adhesive. Restorations were assessed using the United States Public Health Service (USPHS) criteria at 1 week (baseline) and 6, 12, and 24 months. Survival rate, periodontal parameters, dentin hypersensitivity (DH), and aesthetics were also evaluated., Results: After 24 months, only the MH + TE group did not lose any restoration, with no significant differences between groups. For surface roughness parameter, MH presented 83.3% of the restorations scoring Bravo, whereas NP presented 48.5% of the restorations scoring Bravo. All groups presented restorations with marginal discoloration. All periodontal parameters behaved similarly, regardless of the restorative material. All groups presented significant reductions of dentin hypersensitivity and improved aesthetic perceptions (p < 0.05)., Conclusion: Both resin composites and adhesives tested can be combined for partial restorations to treat CDs., Clinical Relevance: This new restorative-surgical protocol to treat CDs presents satisfactory outcomes. The partial restorations can be successfully executed with both combinations of adhesives and resin composites evaluated in this investigation. TRN : ClinicalTrial.gov: NCT03215615; registration date July 12, 2017., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A systematic review and network meta-analysis was performed to provide evidence for the best polishing protocol for different types of resin composites to minimize surface roughness. A search was performed in PubMed, Scopus, Web of Science, LILACS, BBO, EMBASE, and Cochrane Library on July 2, 2019 (updated in December, 2020). In vitro studies that included at least two systems for polishing resin composites and analyzed surface roughness were included. The risk of bias was evaluated. A random-effects Bayesian-mixed treatment comparison model was used to compare surface roughness in resin composites with the different types of polishers. Surface under the cumulative ranking curve (SUCRA) analysis was performed to rank the probability for the best polishing system. After removal of duplicates, title and abstract screening yielded 34 studies. Network meta-analysis was not possible for hybrid and microhybrid composites. SUCRA analysis showed that abrasive paper discs allowed greater surface smoothness for nanohybrid and nanofill composites to a probability of between 83% and 91.6%. Silicon carbide brush had a 78.2% probability of being the best system for microfill composites. The use of abrasive paper disc polishers showed a favorable result in nanofill and nanohybrid resin composites. Silicon carbide brush has a greater chance of promoting a smoother surface for microfill resin composites., (© 2023 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous-mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid leukemia predisposition and thrombopoietic defects.

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is a pressing demand for more effective drugs. This study examined potential therapeutic effects of growth hormone secretagogues (GHSs), a large family of synthetic compounds, as possible candidates for the treatment of ALS. Human neuroblastoma cells expressing the SOD1-G93A mutated protein (SH-SY5Y SOD1 G93A cells) were incubated for 24 h with H 2 O 2 (150 µM) in the absence, or presence, of GHS (1 µM), in order to study the protective effect of GHS against increased oxidative stress. The two GHSs examined in this study, hexarelin and JMV2894, protected cells from H 2 O 2 -induced cytotoxicity by activating molecules that regulate apoptosis and promote cell survival processes. These findings suggest the possibility of developing new GHS-based anti-oxidant and neuroprotective drugs with improved therapeutic potential. Further investigations are required for the following: (i) to clarify GHS molecular mechanisms of action, and (ii) to envisage the development of new GHSs that may be useful in ALS therapy.

Amyotrophic lateral sclerosis (ALS) arises from neuronal death due to complex interactions of genetic, molecular, and environmental factors. Currently, only two drugs, riluzole and edaravone, have been approved to slow the progression of this disease. However, ghrelin and other ligands of the GHS-R1a receptor have demonstrated interesting neuroprotective activities that could be exploited in this pathology. Ghrelin, a 28-amino acid hormone, primarily synthesized and secreted by oxyntic cells in the stomach wall, binds to the pituitary GHS-R1a and stimulates GH secretion; in addition, ghrelin is endowed with multiple extra endocrine bioactivities. Native ghrelin requires esterification with octanoic acid for binding to the GHS-R1a receptor; however, this esterified form is very labile and represents less than 10% of circulating ghrelin. A large number of synthetic compounds, the growth hormone secretagogues (GHS) encompassing short peptides, peptoids, and non-peptidic moieties, are capable of mimicking several biological activities of ghrelin, including stimulation of GH release, appetite, and elevation of blood IGF-I levels. GHS have demonstrated neuroprotective and anticonvulsant effects in experimental models of pathologies both in vitro and in vivo . To illustrate, some GHS, currently under evaluation by regulatory agencies for the treatment of human cachexia, have a good safety profile and are safe for human use. Collectively, evidence suggests that ghrelin and cognate GHS may constitute potential therapies for ALS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Genome editing using CRISPR/Cas9 has become a powerful tool in zebrafish to generate targeted gene knockouts models. However, its use for targeted knock-in remains challenging due to inefficient homology directed repair (HDR) pathway in zebrafish, highlighting the need for efficient and cost-effective screening methods.  RESULTS: Here, we present our fluorescent PCR and capillary electrophoresis based screening approach for knock-in using a single-stranded oligodeoxynucleotide donor (ssODN) as a repair template for the targeted insertion of epitope tags, or single nucleotide changes to recapitulate pathogenic human alleles. For the insertion of epitope tags, we took advantage of the expected change in size of the PCR product. For point mutations, we combined fluorescent PCR with restriction fragment length polymorphism (RFLP) analysis to distinguish the fish with the knock-in allele. As a proof-of-principle, we present our data on the generation of fish lines with insertion of a FLAG tag at the tcnba locus, an HA tag at the gata2b locus, and a point mutation observed in Gaucher disease patients in the gba gene. Despite the low number of germline transmitting founders (1-5%), combining our screening methods with prioritization of founder fish by fin biopsies allowed us to establish stable knock-in lines by screening 12 or less fish per gene., Conclusions: We have established a robust pipeline for the generation of zebrafish models with precise integration of small DNA sequences and point mutations at the desired sites in the genome. Our screening method is very efficient and easy to implement as it is PCR-based and only requires access to a capillary sequencer., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aquifer storage and recovery (ASR) is an important water resources management technique that involves the injection of a large volume of water underground. For the successful implementation of an ASR project, a target aquifer should have a sufficient injection capacity, which is the maximum volume of water that can be safely injected. In nature, no aquitard is perfectly impermeable, and inter-aquifer leakage may have a major impact on injection capacity. Despite the importance of determining the injection capacity for ASR planning, there is no quantitative methodology that estimates the injection capacity of leaky aquifers. In this study, we first develop a solution for injection capacity with inter-aquifer leakage based on the Hantush - Jacob solution, and conduct a comprehensive sensitivity analysis to elucidate the influence of inter-aquifer leakage on injection capacity. From the sensitivity analysis, we show that inter-aquifer leakage can impact injection capacity by more than one order of magnitude, depending on the hydrogeological and operational parameters. We then develop a practical mapping methodology that estimates the injection capacity of leaky aquifers. We demonstrate the proposed methodology by applying it to a potential ASR site in Minnesota, USA, where ASR is considered as a solution to alleviate groundwater contamination by PFAS chemicals. The case study results reveal significant spatial variability in injection capacity over the study area and show an average increase in the injection capacity of about 26% compared to that in the nonleaky scenario. We also analyze the uncertainty in the estimated injection capacity due to the variability of aquitard properties and show that the variability of aquitard vertical hydraulic conductivity leads to a larger uncertainty in the estimated injection capacity than does the variability of aquitard thickness. This study elucidates the effects of inter-aquifer leakage on injection capacity and provides a practical methodology for injection capacity mapping., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reporterggd in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study investigated modifications of microRNA expression profiles in knee synovial fluid of patients with osteoarthritis (OA) and rupture of the anterior cruciate ligament (ACL). Twelve microRNAs (26a-5p, 27a-3p, let7a-5p, 140-5p, 146-5p, 155-5p, 16-5p,186-5p, 199a-3p, 210-3p, 205-5p, and 30b-5p) were measured by real-time quantitative polymerase chain reaction (RT-qPCR) in synovial fluids obtained from 30 patients with ACL tear and 18 patients with knee OA. These 12 miRNAs were chosen on the basis of their involvement in pathological processes of bone and cartilage. Our results show that miR-26a-5p, miR-186-5p, and miR-30b-5p were expressed in the majority of OA and ACL tear samples, whereas miR-199a-3p, miR-210-3p, and miR-205-5p were detectable only in a few samples. Interestingly, miR-140-5p was expressed in only one sample of thirty in the ACL tear group. miR-140-5p has been proposed to modulate two genes (BGN and COL5A1100) that are involved in ligamentous homeostasis; their altered expression could be linked with ACL rupture susceptibility. The expression of miR-30b-5p was higher in OA and chronic ACL groups compared to acute ACL samples. We provide evidence that specific miRNAs could be detected not only in synovial fluid of patients with OA, but also in post-traumatic ACL tears.

ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) is an essential splicing factor involved in 3' splice-site recognition as a component of both the major and minor spliceosomes that mediate the splicing of U2-type (major) and U12-type (minor) introns, respectively. Studies of ZRSR2 -depleted cell lines and ZRSR2 -mutated patient samples revealed its essential role in the U12-dependent minor spliceosome. However, the role of ZRSR2 during embryonic development is not clear, as its function is compensated for by Zrsr1 in mice. Here, we utilized the zebrafish model to investigate the role of zrsr2 during embryonic development. Using CRISPR/Cas9 technology, we generated a zrsr2 -knockout zebrafish line, termed zrsr2 hg129/hg129 (p.Trp167Argfs*9) and examined embryo development in the homozygous mutant embryos. zrsr2 hg129/hg129 embryos displayed multiple developmental defects starting at 4 days post fertilization (dpf) and died after 8 dpf, suggesting that proper Zrsr2 function is required during embryonic development. The global transcriptome analysis of 3 dpf zrsr2 hg129/hg129 embryos revealed that the loss of Zrsr2 results in the downregulation of essential metabolic pathways and the aberrant retention of minor introns in about one-third of all minor intron-containing genes in zebrafish. Overall, our study has demonstrated that the role of Zrsr2 as a component of the minor spliceosome is conserved and critical for proper embryonic development in zebrafish.

Systematic review and network meta-analyses were performed to answer the question: Do intraradicular chemical pretreatments affect the bond strength of the adhesive interface between dentine and fiber post cements? A literature search was performed in PubMed, Scopus, Web of Science, LILACS, BBO, and Cochrane Library in October 2018 (updated September 2021). In vitro studies that compared the bond strength assessed by push-out tests following at least two dentine chemical treatments prior to fiber post cementation were included. Risk of bias was evaluated. A random-effects Bayesian-mixed treatment comparison model was used to compare push-out bond strength of different chemical pretreatments. SUCRA (surface area under the cumulative ranking) analysis was performed to rank the pretreatments. After removing duplicates and screening titles and abstracts, 61 studies remained. SUCRA analysis showed that the best bond strength values for self-etch, etch-and-rinse, and self-adhesive cements were ethyl acetate (SUCRA: 99.8%), low concentration NaOCl (SUCRA: 83.4%), and grape seed extract (SUCRA: 97.6%), respectively. According to the SUCRA rankings, ethanol was in a good position for all adhesive strategies (SUCRA: 78.6%). The use of chemical pretreatments in intraradicular dentine of endodontically treated teeth depends on the adhesive and cementation strategy. The pretreatment generally associated with the highest bond strength was ethanol., (© 2022 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

Statement of Problem: A fiber post is indicated when there is a significant loss of tooth structure and additional support for the restoration is needed. However, whether the use of a glass fiber post affects the fracture susceptibility of the restored anterior teeth is unknown., Purpose: The purpose of this systematic review and meta-analysis was to evaluate the fracture resistance of endodontically treated and restored anterior teeth and to answer the research question, "Does the use of a fiber post influence the fracture resistance of endodontically treated and restored anterior teeth compared with alternative restorative treatments?", Material and Methods: A search was performed in PubMed, Scopus, Web of Science, LILACS, BBO, Cochrane Library, and Embase databases without date and/or language restrictions (updated in July, 2020). In vitro studies comparing the fracture strength of endodontically treated and restored anterior teeth with and without fiber posts were included. The risk of bias was evaluated by using the previous meta-analyses of in vitro studies. The results were presented as standardized mean difference with a 95% confidence interval. Statistical heterogeneity of treatment effects between studies was assessed using the Cochran Q test and the I2 inconsistency test, and values greater than 50% were considered indicative of substantial heterogeneity., Results: After the removal of duplicates and title and abstract screening, 31 studies remained. Seventeen were considered low risk of bias, 10 were medium risk of bias, and 4 were high risk of bias. Meta-analysis comparing control and experimental groups favored the use of a fiber post in endodontically treated teeth with some types of restoration to improve fracture resistance (standardized mean difference= 0.5 [0.08; 0.92]); a glass fiber post was also favored (standardized mean difference=0.92 [0.43; 1.42]); for veneer preparations and teeth with cervical cavities, a fiber post increases the fracture strength (standardized mean difference= 0.74 [0.01; 1.47]; 1.18 [0.35; 2.02], respectively)., Conclusions: The use of glass fiber posts increases the fracture resistance of endodontically treated and restored teeth., (Copyright © 2020 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

The aim of this clinical report is to present a possible alternative treatment, with 24-month follow-up, for restoring tooth loss due to extensive erosive tooth wear. A 21-year-old male patient, complaining of intense sensitivity in the maxillary posterior teeth, and presenting severe wear on maxillary premolar and molar teeth due to gastroesophageal reflux, sought care in the university clinics. The planned treatment was to refer for medical treatment and perform restorations with the high-viscosity glass ionomer cement Equia Forte (GC Corporation, Tokyo, Japan), aiming to restore the dental anatomy and to consequently decrease the pain symptomatology. A silicone guide, obtained from a diagnostic waxing, was used during the restorative approach considering the patient's occlusion. After all the clinical steps of the restorative technique, an occlusal adjustment of restorations was performed. During monthly recalls up to 24 months, the treatment was stable and in service. In addition, the patient reported no pain and improved chewing, leading to a better quality of life., (©Operative Dentistry, 2022.)

Background: Evaluate the use of collagen matrix (CM) as adjunctive to coronally advanced flap (CAF versus CAF + CM) to treat gingival recession (GR) associated with non-carious cervical lesion-combined defects (CDs)., Methods: Sixty-two patients presenting 62 CDs (RT1 GR and non-carious cervical lesion (NCCLs) were randomly allocated to either CAF group (n = 31): partial restoration of the NCCL and CAF; or to CAF + CM group (n = 31): partial restoration of the NCCL and CAF associated with CM. Clinical, esthetic, patient-centered outcomes, and restorative parameters were assessed., Results: After 12 months, CD coverage were 55.2% for CAF and 54.4% for CAF + CM (P = 0.8). Recession reduction were 1.9 ± 0.8 mm for CAF and 2.0 ± 0.7 mm for CAF + CM (P = 0.6). CAF+CM resulted in higher increase in keratinized tissue (KT) width (CAF: 0.3 ± 0.7 mm; CAF + CM: 0.9 ± 0.8 mm; P = 0.004) and KT thickness gain (CAF: 0.1 ± 0.3 mm; CAF + CM: 0.7 ± 0.2 mm; P = 0.001). Both treatments presented low postoperative pain and resulted in esthetics improvements. In addition, no restoration was lost, 27.4% showed a reduction of the superficial polishing, and 8% showed marginal staining, but still clinically acceptable., Conclusion: Partial resin composite restoration (with the apical limit up to 1 mm of the estimated CEJ) and CAF alone or combined with CM are suitable for treating CDs. The use of CM provided additional benefits in terms of KT width and thickness gain. (NCT03341598)., (© 2021 American Academy of Periodontology.)

Combined AntiRetroviral Treatments (cARTs) used for HIV infection may result in varied metabolic complications, which in some cases, may be related to patient genetic factors, particularly microRNAs. The use of monozygotic twins, differing only for HIV infection, presents a unique and powerful model for the controlled analysis of potential alterations of miRNAs regulation consequent to cART treatment. Profiling of 2578 mature miRNA in the subcutaneous (SC) adipose tissue and plasma of monozygotic twins was investigated by the GeneChip® miRNA 4.1 array. Real-time PCR and ddPCR experiments were performed in order to validate differentially expressed miRNAs. Target genes of deregulated miRNAs were predicted by the miRDB database (prediction score > 70) and enrichment analysis was carried out with g:Profiler. Processes in SC adipose tissue most greatly affected by miRNA up-regulation included (i) macromolecular metabolic processes, (ii) regulation of neurogenesis, and (iii) protein phosphorylation. Furthermore, KEGG analysis revealed miRNA up-regulation involvement in (i) insulin signaling pathways, (ii) neurotrophin signaling pathways, and (iii) pancreatic cancer. By contrast, miRNA up-regulation in plasma was involved in (i) melanoma, (ii) p53 signaling pathways, and (iii) focal adhesion. Our findings suggest a mechanism that may increase the predisposition of HIV+ patients to insulin resistance and cancer.

Objectives: Quantification of collagen degradation is an important parameter to evaluate dentin caries for preventive aid.. Evaluate preventive methods against root collagen degradation by the hydroxyproline assay (HYP) and microradiography technique (MRT)., Methodology: Five bovine root dentin blocks were obtained and subjected to an artificial demineralization process by acetate buffer (pH 5) to induce carious lesion formation. Samples were subjected to the following therapeutic treatments: 1) 0.12% chlorhexidine for 1 min, 2) 2% fluoride for 1 min, 3) Nd:YAG Laser (400 μm diameter optical fiber, 10 Hz frequency, 60 mJ/pulse energy, 48 J/cm2 energy density, in noncontact mode for 10 s), 4) deionized water (control) for 1 min, 5) MRT control group (without treatment and removal of collagen). Samples were exposed to degradation by a collagenase enzyme for five days. The enzyme solution was collected, by colorimetry in a spectrophotometer, from the collagen matrix for the hydroxyproline release analysis. The same samples were subjected to an additional two days of demineralization to induce the progression of mineral loss. Samples were analyzed by MRT for the visualization of their degraded areas (estimation of lesion depth and mineral loss). ANOVA was applied to compare hydroxyproline release rates. MRT data were subjected to the Kruskal-Wallis test, followed by the Dunn's test. Comparisons between the initial five-day and the subsequent two-day demineralization processes were performed by repeated t-test or Wilcoxon (p<0.05) measurements., Results: The amount of HYP released from the dentin samples failed to show significant differences among the groups (p=0.09). Fluoride and chlorhexidine were able to interact with the samples, reducing the progression of dentin caries after removal of the demineralized organic matrix. CHX was the only treatment able to show significant lower lesion depth than the negative control., Conclusion: Chlorhexidine and fluoride were effective in reducing root caries progression.

Objectives: This study evaluated the effect of deep margin elevation (DME) and restorative materials (leucite-reinforced glass-ceramics [C] vs. indirect resin composite [R]) on the fatigue behavior and stress distribution of maxillary molars with 2-mm deep proximal margins restored with MOD inlay., Methods: Fifty-two extracted human third molars were randomly assigned into four groups (n = 13): C; DME + C; R; and DME + R. Inlays were fabricated in CAD-CAM and bonded to all teeth. The fatigue behavior was assessed with the stepwise stress test (10,000 cycles/step; step = 50 N; 20 Hz; initial load = 200 N). Fatigue failure loads and the number of cycles were analyzed with 2-way ANOVA and Tukey's test (p < 0.05) and Kaplan-Meier survival plots. The stress distribution was assessed with finite element analysis. The models were considered isotropic, linear, and homogeneous, and presented bonded contacts. A tripod axial load (400 N) was applied to the occlusal surface. The stress distribution was analyzed with the maximum principal stress criterion., Results: For fatigue, there was no difference for DME factor (p > 0.05). For the material factor, the load and number of cycles for failure were statistically higher in the R groups (p < 0.05). The finite element analysis showed that resin composite inlays concentrated more stress in the tooth structure, while ceramic inlays concentrated more stress in the restoration. Non-reparable failures were more frequent in the resin composite inlays groups., Conclusions: DME was not negative for fatigue and biomechanical behaviors. Resin composite inlays were more resistant to the fatigue test, although the failure mode was more aggressive., Clinical Significance: DME does not impair mechanical behavior. Resin composite inlays failed at higher loads but with a more aggressive failure mode., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The current pandemic associated with SARS-CoV-2 has negatively influenced several activities, including teaching in Operative Dentistry. The aim of this study was to evaluate the influence of knowledge in Operative Dentistry on undergraduate students' perception related to personal life and return to clinical practices classes during pandemic., Materials and Methods: The present research was a cross-sectional, observational, and qualitative survey. The 16-item based questionnaire was sent to undergraduate students in 2020, which were divided into two groups, according to the Operative Dentistry knowledge: G1-not started clinical practice; G2-already started or completed clinical practice. Questions were focused on the impact of the pandemic in relation to their personal lives and return to clinical practice classes. Chi-square association test was performed using the SigmaPlot 12.0 software ( P ≤ 0.05)., Results: The response rate was 55.5% for G1 and 44.4% for G2. Regarding the questions related to personal life, G1 demonstrated higher percentages of fear of contracting the virus during theoretical classes. Same observations were found when students answered about their fear of contracting coronavirus during the clinical practice classes. However, G2 presented the highest agreement responses for the preparedness feeling to return to theoretical classroom, clinical practice classes, and the possibility of applying online learning., Conclusions: In general, students' knowledge had little influence on perception of personal life. However, students who have more knowledge in operative dentistry presented more security about returning to clinical classes., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Education and Health Promotion.)

Background: The first clinically detectable stage of caries lesion is a non-cavitated white spot lesion (WSL). The detection of early stages of caries lesions allows non-invasive management by fluoride usage, oral hygiene and diet control. There is a lack of information in the literature regarding the prevalence of these caries lesions in preschool children, which is important especially for public health strategies., Objective: The aim of this study was to conduct a systematic review with meta-analysis to verify the WSLs prevalence in primary teeth of preschool children., Methods: A literature search with MEDLINE/PubMed, Scopus, Web of Science, and Open Gray databases was conducted. Included studies fulfilled the eligibility criteria. Meta-analyses were performed using random effects model, for prevalence of pooled WSLs and subgroups analyses., Results: The search strategy identified 4922 potentially relevant articles, with final inclusion of 16 studies. The pooled prevalence of WSLs in primary teeth was 14.0% (95% CI: 8.0-24.0), without publication bias (p=0.2668). For subgroup analyses, an increase in WSLs prevalence for children of low-income economy (24.0%; 95% CI: 20.0-28.0), for age >31 months (22.0%; 95% CI: 12.0-37.0), for validated visual criteria assessment (20.0%; 95% CI: 11.0-33.0), and for tactile assessment with ball-ended probe (26.0%; 95% CI: 11-50.0) were detected., Conclusion: It is suggested that the prevalence of WSLs in primary teeth of preschool children increases in countries with low income economy, with age greater than 31 months or texture assessment with visual validated criteria or ball-ended probe. PROSPERO Registration: Protocol number #CDR42017078434., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

RUNX1 is essential for the generation of hematopoietic stem cells (HSCs). Runx1-null mouse embryos lack definitive hematopoiesis and die in mid-gestation. However, although zebrafish embryos with a runx1 W84X mutation have defects in early definitive hematopoiesis, some runx1W84X/W84X embryos can develop to fertile adults with blood cells of multilineages, raising the possibility that HSCs can emerge without RUNX1. Here, using 3 new zebrafish runx1-/- lines, we uncovered the compensatory mechanism for runx1-independent hematopoiesis. We show that, in the absence of a functional runx1, a cd41-green fluorescent protein (GFP)+ population of hematopoietic precursors still emerge from the hemogenic endothelium and can colonize the hematopoietic tissues of the mutant embryos. Single-cell RNA sequencing of the cd41-GFP+ cells identified a set of runx1-/--specific signature genes during hematopoiesis. Significantly, gata2b, which normally acts upstream of runx1 for the generation of HSCs, was increased in the cd41-GFP+ cells in runx1-/- embryos. Interestingly, genetic inactivation of both gata2b and its paralog gata2a did not affect hematopoiesis. However, knocking out runx1 and any 3 of the 4 alleles of gata2a and gata2b abolished definitive hematopoiesis. Gata2 expression was also upregulated in hematopoietic cells in Runx1-/- mice, suggesting the compensatory mechanism is conserved. Our findings indicate that RUNX1 and GATA2 serve redundant roles for HSC production, acting as each other's safeguard., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Evidence regarding the effect of the onlay preparation design for different CAD/CAM restorative materials considering the preservation of cusps is lacking. Molars were 3D-modeled in four preparation designs for onlay restoration: traditional design with functional cusp coverage (TFC), non-retentive design with functional cusp coverage (NFC), traditional design with non-functional cusp coverage (TNFC) and non-retentive design with non-functional cusp coverage (NNFC). The restorations were simulated with two CAD/CAM restorative materials: LD-lithium disilicate (IPS e.max CAD) and RC-resin composite (GrandioBloc). A 100 N axial load was applied to the occlusal surface, simulating the centric contact point. Von Mises (VM) and maximum principal (Pmax) stress were evaluated for restorations, cement layer and dental substrate. The non-retentive preparation design reduced the stress concentration in the tooth structure in comparison to the conventional retentive design. For LD onlays, the stress distribution on the restoration intaglio surface showed that the preparation design, as well as the prepared cusp, influenced the stress magnitude. The non-retentive preparation design provided better load distribution in both restorative materials and more advantageous for molar structure. The resin composite restoration on thenon-functional cusp is recommended when the functional cusp is preserved in order to associate conservative dentistry and low-stress magnitude.

Throughout their lifetime, fish maintain a high capacity for regenerating complex tissues after injury. We utilized a larval tail regeneration assay in the zebrafish Danio rerio, which serves as an ideal model of appendage regeneration due to its easy manipulation, relatively simple mixture of cell types, and superior imaging properties. Regeneration of the embryonic zebrafish tail requires development of a blastema, a mass of dedifferentiated cells capable of replacing lost tissue, a crucial step in all known examples of appendage regeneration. Using this model, we show that tail amputation triggers an obligate metabolic shift to promote glucose metabolism during early regeneration similar to the Warburg effect observed in tumor forming cells. Inhibition of glucose metabolism did not affect the overall health of the embryo but completely blocked the tail from regenerating after amputation due to the failure to form a functional blastema. We performed a time series of single-cell RNA sequencing on regenerating tails with and without inhibition of glucose metabolism. We demonstrated that metabolic reprogramming is required for sustained TGF-β signaling and blocking glucose metabolism largely mimicked inhibition of TGF-β receptors, both resulting in an aberrant blastema. Finally, we showed using genetic ablation of three possible metabolic pathways for glucose, that metabolic reprogramming is required to provide glucose specifically to the hexosamine biosynthetic pathway while neither glycolysis nor the pentose phosphate pathway were necessary for regeneration., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, long-term safety and efficacy of androgen administration has yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe and economical. There are, however, few clinical studies, which have focused on effects of androgen therapy on pre- and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological tissues., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with coronavirus disease 2019 (COVID-19) are often treated at home given the limited healthcare resources. Many patients may have sudden clinical worsening and may be already compromised at hospitalisation. We investigated the burden of lung involvement according to the time to hospitalisation., Methods: In this observational cohort study, 55 consecutive COVID-19-related pneumonia patients were admitted to the Emergency Medicine Unit. Groups of lung involvement at computed tomography were classified as follows: 0 (<5%), 1 (5%-25%), 2 (26%-50%), 3 (51%-75%) and 4 (>75%). We also investigated in-hospital death and the predictive value of Yan-XGBoost model and PREDI-CO scores for death., Results: The median age was 74 years and 34 were men. Time to admission increased from 2 days in group 0 to 8.5-9 days in groups 3 and 4. A progressive increase in LDH, CRP and d-dimer was found across groups, while a decrease of lymphocytes paO 2 /FiO 2 ratio and SpO 2 was found. Ten (18.2%) patients died during the in-hospital staying. Patients who died were older, with a trend to lower lymphocytes, a higher d-dimer, creatine phosphokinase and troponin T. The Yan-XGBoost model did not accurately predict in-hospital death with an AUC of 0.57 (95% confidence interval [CI] 0.37-0.76), which improved after the addition of the lung involvement groups (AUC 0.68, 95%CI 0.45-0.90). Conversely, a good predictive value was found for the original PREDI-CO score with an AUC of 0.76 (95% CI 0.58-0.93) which remained similar after the addition of the lung involvement (AUC 0.76, 95% CI 0.57-0.94)., Conclusion: We found that delayed hospital admission is associated with higher lung involvement. Hence, our data suggest that patients at risk for more severe disease, such as those with high LDH, CRP and d-dimer, should be promptly referred to hospital care., (© 2021 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Aim: This study aimed to evaluate the effect of polymerization with either a monowave (MW) or a polywave (PW) light-curing unit (LCU) on the degree of conversion (DC) and marginal adaptation following thermomechanical aging of an ormocer bulk-fill resin composite (RC) (Admira fusion X-tra Bulk Fill - AB), a methacrylate-based bulk-fill RC (Tetric N-Ceram Bulk Fill - TB) and a conventional RC (Tetric N-Ceram - TC). Methods: DC was assessed in five samples of each RC using Fourier transform infrared spectroscopy. For determination of marginal adaptation, standard preparations were made in 60 bovine incisors, divided into three groups, according to the RC. The bulk-fill RC was inserted in a single increment of 4 mm. In contrast, the conventional RC was inserted in three increments. Marginal gap was evaluated after thermomechanical aging. Data were analyzed using a two-way analysis of variance (ANOVA) and Tukey's tests for multiple comparisons ( α  = 0.05). Results: The two-way ANOVA showed a significant effect ( p <.05) of the RC factor but not of the LCU factor. The Tukey test showed that TB had the significantly lowest DC followed by TC, and with AB having the significantly highest DC. For the marginal adaptation, a significant effect was found for the LCU factor and the for the interaction RC × LCU ( p <.05). Groups light-cured with PW showed significantly wider marginal gaps than MW. TC presented wider marginal gaps (17.36 µm) when cured with PW than when cured with MW (13.05 µm). The two bulk-fill RC resulted in similar marginal gap formation to each other. Conclusion: The ormocer-based bulk-fill RC showed a higher DC than the methacrylate-based bulk-fill RC but similar marginal adaptation. The LCU, MW or PW, had no significant influence on the DC, and no relevance on the marginal adaptation., Competing Interests: The authors report no conflict of interest., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Severe tetracycline staining may affect the esthetics of teeth and the self-esteem of patients. This case report describes minimally invasive treatment with dental bleaching and direct restorations to improve the esthetics of tetracycline-stained teeth in a 44-year-old woman. All of the patient's teeth were affected by grayish brown staining, and the maxillary central incisors demonstrated incisal wear. The buccal angulation of the anterior teeth and the patient's Class II skeletal profile hindered the use of direct or indirect veneer restorations. The proposed treatment was home bleaching with 10% carbamide peroxide applied in a soft vinyl tray, which was worn overnight for the first 3 months and 2 hours daily for the next 3 months (total treatment time of 6 months). Afterward, a single session of in-office bleaching with 37% hydrogen peroxide was performed over resistant bands of staining observed at the cervical thirds of the teeth. Fourteen days after the in-office bleaching treatment, composite resin restorations were placed at the incisal areas of the maxillary central incisors and the cervical areas of the central incisors, lateral incisors, and canines to treat the incisal wear and mask the remaining dental discoloration. In some cases, minimally invasive treatment with tooth bleaching might be indicated for the esthetic treatment of teeth severely stained by tetracycline, although this approach presents limitations. In the present case, the patient was satisfied with her smile after the treatment protocol was completed, and the results remained stable after 12 months. The patient reported an improved quality of life after treatment., Competing Interests: The authors report no conflicts of interest pertaining to any of the products or companies discussed in this article.