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Objectives: The quality of life in patients undergoing radical cystectomy and urinary diversion is gaining importance. Nowadays a broad consensus about the best urinary diversion does not exist. This study presents an all-round analysis of the impact of two types of urinary diversion on life's psycho-social aspects in patients undergoing radical cystectomy., Methods: This is an observational, single-centre, prospective study. Eligible participants underwent radical cystectomy and urinary diversion for bladder cancer in our department from January 2020 and February 2024. Of 130 included patients, 90 (45 with Bricker's ureteroileocutaneostomy and 45 received orthotopic bladder replacement) patients were matched and the study groups were well balanced for the baseline-matched variables. Patients completed 4 questionnaires (EORTC QLQ-C30, PGWBI, HADS, PSQI) at three different times: before the surgical procedure, and at 3 and 12 months., Results: Time shows a statistically significant effect (p < 0.0005) on four of the five functional scales explored (Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning), and for all the nine symptoms/items' scales (p < 0.0005) and the Global Health Status (p = 0.003) in EORTC QLQ-C30. Neobladder's group shows a statistically significant improvement on the scales of Physical Functioning, Role Functioning, and Social Functioning, and for symptoms of nausea (p = 0.0027), pain (p = 0.0005), dyspnea (p = 0.012), insomnia (p = 0.004), constipation (p = 0.003)., Conclusion: We do not find a better urinary diversion in absolute terms. Neobladder obtained better results only for specific items and features. The urinary diversion's choice must be made in concert by the patient, the caregiver, and health professionals with adequate counseling., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Objective: This study aimed to assess the treatment quality factors associated with the risk of radiographic detection of apical periodontitis (AP) in root-filled teeth (RFT) on CBCT images., Methods: Two hundred eighty-five CBCT scans of patients (range 18-60, mean 35.1) years old were selected from a pool of CBCT scans which were taken from 2016-2022. Gender and age were recorded. The presence/absence of AP, unfilled canal, perforation, zipping and ledge and homogenous/nonhomogeneous root canal filling (RCF), adequate/inadequate coronal restoration and under/over filled RCF and those within 0-2 mm from the radiographic apex were recorded for RFTs. Kappa was used to assess intra-consensus reliability. Chi-square and Binary logistic regression were used to assess and predict risk factors related to the detection of AP. A significant difference was set at p<0.05., Results: AP was present in 81.5% of RFTs. No significant difference was present in the AP prevalence in RFT between males and females, maxilla and mandible, right and left sides, RFT with adequate and inadequate coronal restoration and RFT with/without zipping and ledge and between RFT with overfilled and those with RCF end within 0-2 mm from the radiographic apex (p>0.05), respectively. Significantly higher AP prevalence was present in RFT with unfilled canal, perforations, non-homogenous and underfilled RCF (p<0.05), respectively. The odds of AP detection were 2.02, 5.5, 2 and 1.98 times higher in RFT with unfilled canal, perforations, non-homogenous and underfilled RCF, respectively. Intra-consensus reliability was (0.98, 0.95, 0.85, 0.81, 0.88, 0.85 and 0.92) for AP, unfilled canal, perforation, zipping and ledge, homogeneity of RCF, coronal restoration and length of RCF, respectively., Conclusion: The vast majority of teeth with previous root fillings presented with AP. AP detection risk was significantly higher in root-filled teeth with perforation, non-homogeneous, and underfilled root canal filling. Other factors do not influence the radiographic detection of AP in CBCT images. (EEJ-2024-02-042).

A synthetic protocol for the preparation of a new class of morpholino homonucleosides in enantiopure form starting from readily available 1,2-aminoalcohols or glycidol has been developed. Key intermediates of the synthetic sequence are 2-bromomethyl morpholines, diastereoselectively achieved from the corresponding alkenols by palladaelectro-catalyzed alkoxybromination of unactivated alkenes. The so obtained bromo derivatives are in turn susceptible to functionalization with nucleic bases for easy access to morpholino homonucleosides.

Background: Regenerative techniques are increasingly being advocated in endodontic apical surgery (AS) to enhance the healing of periapical lesions. Various grafting and membrane materials are employed as adjuncts to modern AS., Objectives: This systematic review aimed to answer the following PICO question: In patients with apical periodontitis (P) what is the impact of bone grafting with/without barrier membrane materials (I) compared with surgery without grafting materials (C) on the outcome of AS evaluated clinically and radiographically (O)., Methods: A systematic search was conducted in four databases (Embase, Web of Science, PubMed and Cochrane Central Register of Controlled Trials) until 1 August 2023. Google Scholar was also manually searched. Studies with a prospective randomized design were included. Cochrane risk-of-bias (RoB) tool 2.0 assessed bias. Two independent reviewers performed the study selection, data extraction and appraisal of studies. Meta-analysis was performed using R3.5.1 software., Results: From the identified 2582 studies, eight randomized clinical trials were included for meta-analysis. Two studies had low RoB, while six had some concerns. Analysis revealed significantly better outcomes when surgery involved bone regeneration techniques than conventional surgery (OR = 2.18, 95% CI: 1.32-4.31, p = .004). Subgroup analyses on individual grafts (OR = 0.22, 95% CI: -0.99 to 1.44, p = .720) (OR = -0.09, 95% CI: -1.42 to 1.23, p = .885) and membranes (OR = -1.09, 95% CI: -2.94 to 0.76, p = .247) and their combinations (OR = 0.03, 95% CI: -1.50 to 1.55, p = .970) did not yield any significant results. The type of membrane used did not significantly impact the outcome (OR = -1.09, 95% CI: -2.94 to 0.76, p = .247) nor did altering the combination of graft/membrane., Discussion: This systematic review examined the effects of bone grafting with/without membrane placement on the outcome of AS. It highlights the potential advantages of regenerative techniques and the need for further research in this area., Conclusions: Based on current evidence, bone grafting with/without barrier membrane placement significantly improves healing after AS. Subgroup analysis of resorbable membranes or grafting did not significantly influence the outcome. The combination of membrane and graft was also not significant. Future well-designed, randomized controlled trials in this area are essential before these materials can be recommended for routine use to enhance healing outcomes in AS., Registration: PROSPERO (CRD42021255171)., (© 2024 The Authors. International Endodontic Journal published by John Wiley & Sons Ltd on behalf of British Endodontic Society.)

Introduction: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment., Methods and Material: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests., Results: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis., Conclusion: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction The success of root canal treatment (RCTx) relies on the technical quality of the root canal filling, often assessed through radiographic evaluation.Aims This audit aims to evaluate the technical proficiency of Peninsula Dental School (PDS) undergraduate dental students in RCTx, comparing it with established European standards.Design Conducted as a retrospective study, this evaluation focuses on assessing the technical quality of RCTx performed by undergraduate dental students at PDS across various academic years.Setting PDS, a primary care-based dental school in the UK, serves as the focal point for this evaluation.Materials and methods Reviewed 2021-2022 endodontic cases by supervised undergraduates. Analysed radiographs for obturation, voids and errors based on established benchmarks. Randomly selected unbiased cases, assessing voids, filling proximity, missed canals and canal anatomy preservation.Interventions Comparative analysis of RCTx quality between PDS students and counterparts from other dental schools, exemplified by Dublin Dental University Hospital (DDUH).Results Findings revealed that 62.07% of single-rooted and 60% of multi-rooted teeth treated by PDS students met European standards.Discussion The implications highlight the proficiency of PDS students in RCTx, comparing favourably to DDUH.Conclusion Recommendations emphasise conducting regular educational audits in dental schools to continually enhance RCTx techniques and ensure high-quality clinical teaching., (© 2024. The Author(s), under exclusive licence to the British Dental Association.)

Background: The distinction between where the pulp chamber ends and the root canal system begins is poorly defined within the existing literature., Methods: This paper aimed to describe a range of accurate methods to define the transition from pulp chamber to root canal in different first molar root morphologies using micro-focus computed tomography (micro-CT)., Methods: The sample consisted of 86 mandibular and 101 maxillary first molars from the skeletal collections housed in the Department of Anatomy and Histology of the Sefako Makgatho Health Sciences University and the Pretoria Bone Collection. A stepwise approach using the cemento-enamel junction (CEJ) and dedicated landmarks was followed to create an automated cross-sectional slice., Results: Transition from pulp chamber to root canal could be accurately determined on maxillary and mandibular teeth. The occurrence of two separate roots in mandibular molars was 97.7%, with the remaining 2.3% having an additional disto-lingual root, with no mandibular molars displaying fused roots. In the maxillary molars, 92.1% had three separate roots and 7.9% displayed root fusion. Within this group, one tooth displayed a C-shaped root canal configuration and one a mesotaurodont-type morphology., Conclusion: The suggested methodology to determine orifice location was found to be appropriate in all morphological types.

EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR. Herein, we report the design, synthesis and in vitro testing of a series of analogues of the previously identified hit with the aim of exploring the structure-activity relationships (SAR) around this scaffold. The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation.

Introduction: Previous studies on the prevalence of vertical root fractures (VRFs) were based on extracted teeth, or teeth referred for apical surgery. This study examined teeth with an isolated periodontal probing depth (PD) as an indicator of VRF. The primary aim of this study was to investigate the prevalence of vertical root fracture (VRF) and non-VRF among teeth with an isolated probing depth (PD) ≥ 5 mm. The secondary aim was to assess factors associated with VRF by comparing the teeth with and without VRF in the Japanese population., Methods: A total of 288 teeth with an isolated PD ≥ 5 mm were grouped pathologically into 8 groups comprising VRF and non-VRF conditions. A descriptive analysis for age, sex, tooth type, endodontically treated teeth (ETT) versus non-ETT, proximal contacts, PD (depth), PD (broadness and location), restoration type, and presence of a post was performed. Moreover, the associations between these factors and VRFs were investigated using the Chi-square test., Results: The prevalence of VRF was 32%. Lower first molars were the most common tooth type in both VRF (31.5%) and non-VRF groups (29.7%), while premolars were exclusively frequent in VRF (30.2%) and not frequent in non-VRF (7.8%). Narrow buccolingual PD was common in VRF (78.1%) whereas wide PD was frequent in non-VRF (67.1%). ETT, narrow buccolingual PD, tooth type (premolars), restoration type (crown), and the presence of a post showed significant associations with VRF (P ≤ .001)., Conclusions: VRFs may be more prevalent in ETT among the Japanese. Careful assessment is necessary to differentiate VRFs from other conditions when the lower first molars show an isolated PD ≥ 5 mm. When an endodontically treated premolar with a post shows a narrow buccolingual PD, the probability of a VRF may be greater than in other tooth types., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

A new straightforward approach to 1-aryl-2-aminopropanes using easily accessible substrates has been developed. Simple allyl alcohol is shown to be an ideal synthetic equivalent of the C3 propane-1,2-diylium bis-cation synthon in three-component cascade reactions with arenes and sulfonamide nucleophiles to regioselectively afford 1-aryl-2-aminopropanes. The reaction is catalyzed by Cu(OTf) 2 and is expected to involve a Friedel-Crafts-type allylation of the arene, followed by hydroamination.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib., Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival., Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/μL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003)., Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline., Competing Interests: M. Iavarone: speaking/teaching, consultant, and advisory board for Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, Guerbet, EISAI, Roche, and AstraZeneca; C. Soldà: consulting/advisory role for MSD and EISAI; speakers’ bureau for Roche and MSD; C. Yoo: received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol-Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen; and received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceutical, and Chong Kun Dang Pharm.; F. Piscaglia: AstraZeneca, Bayer, Bracco, EISAI, Esaote, Exact Sciences, IPSEN, MSD, Roche, Samsung, and Tiziana Life Sciences; P. Lampertico: advisory board/speaker bureau for BMS, Roche, Gilead Sciences, GSK, AbbVie, MSD, Arrowhead, Alnylam, Janssen, SPRING Bank, MYR, Eiger, Aligos, Antios, and Vir., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Diagnosis is a key aspect in endodontic treatment, in a decade where invasive interventions are misapprehended as social tendency instead of medical necessity. All diagnostic facets should be considered before intending the operative phase. Intraoral endodontic radiology-based diagnosis has been shown to be limited. Periapical X-ray is the most used endodontic imaging, yet it does not provide high accuracy. Traditionally, dentists have been trained to diagnose a cyst by certain aspects (size, shape and appearance); hence, an assumption that teeth are affected by "periapical cyst" were subjected to unnecessary extraction or apicoectomy. The aim of this systematic review is to critically appraise the publications that relate the histological diagnosis of a periapical lesion (considered the gold standard) to intraoral X-ray investigation. Ovid Medline, PubMed, ScienceDirect, Mendeley and Scopus were searched for English-language studies comparing periapical diagnosis obtained by using two techniques (histopathology and X-ray). Sixteen articles were included for the final analysis (qualitative and quantitative evaluation) out of which only two supported the statement that periapical diagnosis can be coherently assessed through periapical imaging. Although there is not enough evidence to deliver a definitive conclusion, there are many publications that refute the diagnosis of a cyst via periapical X-ray.

Multi-target compounds have become increasingly important for the development of safer and more effective drug candidates. In this work, we devised a combined ligand-based and structure-based multi-target repurposing strategy and applied it to a series of hexahydrocyclopenta[c]quinoline compounds synthesized previously. The in silico analyses identified human Carbonic Anhydrases (hCA) and Estrogen Receptors (ER) as top scoring candidates for dual modulation. hCA isoforms IX and XII, and ER subtypes ER⍺ and/or ERβ are co-expressed in various cancer cell types, including breast and prostate cancer cells. ER⍺ is the primary target of anti-estrogen therapy in breast cancer, and the hCA IX isoform is a therapeutic target in triple-negative breast cancer. ER⍺-mediated transcriptional programs and hCA activity in cancer cells promote favorable microenvironments for cell proliferation. Interestingly, several lines of evidence indicate that the combined modulation of these two targets may provide significant therapeutic benefits. Moving from these first results, two additional hexahydrocyclopenta[c]quinoline derivatives bearing a sulfonamide zinc binding group (hCA) and a phenolic hydroxyl (ER) pharmacophoric group placed at the appropriate locations were designed and synthesized. Interestingly, these compounds were able to directly modulate the activities of both hCA and ER targets. In cell-based assays, they inhibited proliferation of breast and prostate cancer cells with micromolar potency and cell type-selective efficacy. The compounds inhibited hCA activity with nanomolar potency and isoform-selectivity. In transactivation assays, they reduced estrogen-driven ER activity with micro-molar potency. Finally, crystal structures of the synthesized ligands in complex with the two targets revealed that the compounds bind directly to the hCA active site, as well as to the ER ligand-binding domain, providing structural explanation to the observed activity and a rationale for optimization of their dual activity. To the best of our knowledge, this work describes the design, synthesis and biological characterization of the first dual modulators of hCA and ER, laying the ground for the structure-based optimization of their multi-target activity., 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 reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy., Materials and Methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population., Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed., Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC., Competing Interests: Disclosure LR has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. ACG has received grants and personal fees from MSD, Eisai, Bayer, and is an advisor for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca, and GSK. MK has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb; has received grants and personal fees from MSD, Eisai, and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, and ONO Pharmaceutical. FPi has received consulting or lecture fees from in the last 2 years from Astrazeneca, Bayer, Bracco, EISAI, ESAOTE, Exact Sciences, IPSEN, MSD, Roche, Samsung, and Tiziana Life Sciences. All other authors have declared no conflicts of interest. Data sharing All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite several efforts in the search for noninvasive biomarkers to provide prognostic information for noninvasive muscle bladder cancer, none have shown significant potential. In this context, standard urinalysis is still necessary to provide many data. This method is an inexpensive, simple, and easy-to-repeat tool to follow-up patients over time. Urinalysis does not fall within study protocols and allows evaluation of the immune activation/response (even if indirectly). As such, this method can certainly provide useful information for prognosis.

Treatment of 4-(2-hydroaminoalkylidenyl)- and 4-(2-hydroxyalkylidenyl)-substituted isoxazol-5(4 H )-ones with catalytic amounts of [RuCl 2 ( p -cymene)] 2 , without any additive, afforded pyrazole- and isoxazole-4-carboxylic acids, respectively. The presence of an intramolecular H-bond in these substrates was the key to divert the classical mechanism toward a ring-opening non-decarboxylative path that is expected to generate a vinyl Ru-nitrenoid intermediate, the cyclization of which affords the rearranged products. A gram scale protocol demonstrated the synthetic applicability of this transformation.

Background: Consensus on the treatment of choice for complicated crown fractures of teeth is limited. Recent guidance recommends vital-pulp-therapy; however, the preferred type is not specified. Higher success rates for pulpotomy compared to pulp-capping have been documented, which suggests pulpotomy may be a preferable option for complicated crown-fractures., Objectives: The purpose of this systematic review was to determine the success rate of pulpotomy (partial and complete) on teeth that suffered complicated crown fractures., Participants: patients who have suffered a complicated crown fracture to an anterior permanent tooth., Intervention: pulpotomy (partial or complete). Comparator: pulp-capping or root canal treatment., Outcome: combined clinical and radiographic success at or after 12 months., Methods: A systematic literature using key search terms was conducted using PubMed, Web of Science and Cochrane-Central-Register-of-Controlled-Trials (CENTRAL) as well as a grey literature search from inception to May 2021 and without language restricted to English. Strict inclusion criteria were applied. A standardized tool with defined criteria to assess the risk of bias in each study was used. For non-randomized comparative trials, the Robins-I tool was used while the Newcastle-Ottawa scale was used for non-comparative non-randomized studies., Results: Seven retrospective clinical studies were included. The studies reported high success rates for pulpotomy with overall success ranges for partial or complete pulpotomy ranging from 75% to 96%. One study compared the success rates of pulpotomy to an alternative treatment option pulp capping (90.9% vs. 67%, respectively). Due to the lack of homogeneity in the included studies, a meta-analysis was not possible., Discussion: This review highlights the limited evidence based for the current guidance on treatment of complicated crown fractures. The findings of the review indicate high success rates for pulpotomy; however, there is a moderate risk of bias and small sample sizes in the included studies with the result that the overall results should be interpreted with caution., Conclusion: Within the limitations of this review, the benefits and high success rates reported for partial pulpotomy suggest this procedure, rather than pulp-capping, should be considered as the treatment of choice for both immature and mature teeth that have suffered complicated crown-fractures., (© 2022 The Authors. International Endodontic Journal published by John Wiley & Sons Ltd on behalf of British Endodontic Society.)

A dimerization/cyclization reaction of 2-benzylamino-phenols for the direct synthesis of the oxazolo-phenoxazine skeleton is reported. The reaction occurs under copper catalysis in the presence of hypervalent iodine(III), giving selectively the 5 H -oxazolo[4,5- b ]phenoxazine compounds. The cascade process, which allows the conversion of the substrates into the tetracyclic products, involves three C-H functionalization steps. Initial oxidation of electron-rich arenes by the hypervalent iodine is essential for the dimerization of substrates, whereas the formation of the five-membered rings is promoted by the copper species. 1-Benzyl-2-phenyl-6-(aryl-benzyl)amino-benzimidazoles are regioselectively obtained using N , N '-dibenzyl-phenylenediamines as starting substrates. The fluorescence emission properties of these classes of products have been evaluated.

Background and Aim: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome., Methods: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS)., Results: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277)., Conclusions: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity., (© 2021 The Authors. Published by Wiley-VCH GmbH.)

Background: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes., Patients and Methods: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed., Results: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047)., Conclusion: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients., Competing Interests: Disclosure AC-G has received grants and personal fees from MSD, Eisai and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. MK has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma and Bristol-Myers Squibb; has received grants and personal fees from MSD, Eisai and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly and ONO Pharmaceutical. AJ reports personal fees from Eisai. All other authors have declared no conflicts of interest. Data sharing Data available on request from the authors., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient., Patients and Methods: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib., Results: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group., Conclusions: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC., Competing Interests: Disclosure The authors have declared no conflicts of interest. Data sharing Data are available upon reasonable request., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Regenerative endodontic procedures (REPs) are intended to repair and regenerate part of the pulp-dentin complex. The aim of this study was to systematically appraise the existing evidence on the effectiveness of REPs on mature teeth with pulp necrosis and apical periodontitis., Methods: Electronic database and hand searches were performed on 8 databases of published and unpublished literature from inception to January 3, 2021, for the identification of randomized controlled trials (RCTs) or prospective clinical trials. The related key words included "regenerative," "pulp revascularization," "revitalization procedure," and "necrotic mature teeth." A random effects meta-analysis was conducted assessing success as the main outcome treatment. Risk of bias was assessed through the Cochrane Risk of Bias 2.0 tool, and the quality of the evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation approach., Results: Of the 337 initial hits, 4 RCTs were eligible for inclusion, whereas 3 were included in the quantitative synthesis. Overall, there was no difference in the relative risk for a successful/unsuccessful treatment outcome between REPs or conventional treatment (3 studies, relative risk = 1.03; 95% confidence interval, 0.92-1.15; P = .61; heterogeneity I 2 = 0.0%, P = .53; prediction interval = 0.51-2.09). Risk of bias ranged from low to raising some concerns, whereas the quality of the evidence was graded as moderate., Conclusions: Based on moderate-quality evidence, REPs appear as a viable treatment alternative for mature necrotic teeth with periapical lesions at present. Furthermore, well-designed RCTs might also provide confirmatory evidence in this respect while also framing a backbone for standardization of the therapeutic protocol of REPs., (Copyright © 2021 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

This study investigated the antibacterial activity, bond strength to dentin (SBS), and ultra-morphology of the polymer-dentin interface of experimental adhesive systems doped with pyrogallol (PY), which is a ubiquitous phenolic moiety that is present in flavonoids and polyphenols. A universal adhesive containing 4-META and 10-MDP was used in this study. PY behaves as an antioxidant and anti-cancerogenic agent and it was incorporated into the adhesive at different concentrations (0.5 and 1 wt.%). The antibacterial activity and SBS were analyzed and the results were statistically analyzed. The ultra-morphology of the polymer-dentin interface was assessed using scanning electron microscopy (SEM). At 24 h, a lower antibacterial activity was observed for the control adhesive compared to those with 0.5% and 1% PY. No difference was seen in SBS between the three groups at 24 h. After 6 months, the SBS of the 0.5% PY adhesive was significantly lower than the other tested adhesives. The specimens created with 1% PY adhesive presented a higher bond strength at six months compared with that found at 24 h. No morphological differences were found at the polymer-dentin interfaces of the tested adhesives. Pyrogallol may be incorporated into modern universal adhesive systems to preserve the polymer-dentin bonding interface and confer a certain degree of antibacterial activity.

Background: The number of voids within the root canal obturation is a relevant parameter to describe the quality of the technique, as well as to predict long-term prognosis. The aim of this study was to evaluate the quality of root canal obturation in curved root canals filled with Thermafil, GuttaCore, GuttaFusion and lateral compaction with AH Plus and EndoSequence BC sealer, by means of percentage of gutta-percha and sealer filled area., Methods: 200 curved canals of mandibular molars were divided in five groups ( n = 40). Each specimen was evaluated at 3, 6 and 9 mm from the apex. A total of 600 samples were analyzed. Obturation was performed with either Thermafil (TH), GuttaCore (GC), GuttaFusion (GF) or lateral compaction (LC), using AH Plus as sealer. In another group EndoSequence BC sealer (BC) was used. Subgroups ( n = 20) were made depending on the use of sonic activation during the placement of the sealer. The percentage of total obturation material was analyzed as an indirect measurement of percentage of voids., Results: GF showed a better performance at the apical level, while GC showed the higher percentage of total obturation at the coronal area. No differences were observed for the activation of sealers in any of the groups. Statistical analysis was performed by using two-way ANOVA. Statistical significance was set at CI: 95% ( p < 0.05)., Conclusions: Sonic activation of sealers did not show any benefit to avoid the presence of voids within obturation of curved canals. Following the manufacturer recommendations, we found that TH did not show benefits when applied to curved canals.

Background & Aims: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, monofocal hepatocellular carcinoma (HCC) is classified as early (BCLC A) irrespective of its size, even though controversies still exist regarding staging and treatment of large tumours. We aimed at evaluating the appropriate staging and treatment for large (>5 cm) monofocal (HCC)., Methods: From the Italian Liver Cancer database, we selected 924 patients with small early monofocal HCC (2-5 cm; SEM-HCC), 163 patients with larger tumours (>5 cm; LEM-HCC) and 1048 intermediate stage patients (BCLC B)., Results: LEM-HCC patients had a worse overall survival (OS) than SEM-HCC (31.0 vs 49.0 months; P < .0001), and this was confirmed at multivariate analysis (HR 1.63, 95% CI 1.29-2.05; P < .0001). The small difference in OS between LEM-HCC and BCLC B patients (31.0 vs 27.0 months; P = .03) disappeared in the multivariate model (HR 0.98, 95% CI 0.77-1.25; P = .89). In all monofocal tumours, treatment was the strongest independent predictor of survival, with a progressively decreasing survival benefit moving from "curative" to "palliative" therapies. The survival of resected patients with LEM-HCC was significantly shorter than that of SEM-HCC (44.0 vs 78.0 months; P = .002), but liver resection provided the highest survival benefit in both groups compared to other treatments., Conclusions: Monofocal HCC larger than 5 cm should not be staged as BCLC A and either a different staging system or a different subgrouping of patients (e.g. BCLC AB) should be used. Liver resection, if feasible, remains the recommended treatment for all these patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Infections of the root canal space involve polymicrobial biofilms and lead to chronic, low grade inflammatory responses arising from the seeding of microbes and by-products. Acute exacerbation and/or disseminating infections occur when established microbial communities undergo sudden changes in phenotypic behaviour., Methods: Within clinical endodontic infections, we assessedcategorical determinants comprising, and changing microbial composition of, chronic polymicrobial infections and their association with amoebae. After standardised assessment, primary or secondary infections underwent sampling and DNA processing, targeting bacteria, fungi and amoebae, including 16S high-throughput sequencing. After taxonomic assignment, community composition was correlated with clinical signs and symptoms. Diversity and abundance analyses were carried out in relation to the presence of non-bacterial amplicons., Results: Clinical specimens revealed two distinct community clusters, where specific changes correlated with clinical signs. An association between the compositions of microbiomes was found between these groups and the presence of Entamoeba gingivalis in 44% of cases. When amoebae were present in endodontic infections, we demonstrate changes in microbial community structure that mirror those observed in treatment-resistant or recurrent infections., Conclusions: Amoeba are present in endodontic infections at a high prevalence, and may promote increased virulence by enrichment for phagocytosis-resistant bacteria.

The chemical reactivity of cannabidiol is based on its ability to undergo intramolecular cyclization driven by the addition of a phenolic group to one of its two double bonds. The main products of this cyclization are Δ 9 -THC ( trans -Δ-9-tetrahydrocannabinol) and Δ 8 -THC ( trans -Δ-8-tetrahydrocannabinol). These two cannabinoids are isomers, and the first one is a frequently investigated psychoactive compound and pharmaceutical agent. The isomers Δ 8 - iso -THC ( trans -Δ-8- iso -tetrahydrocannabinol) and Δ 4(8) - iso -THC ( trans -Δ-4,8- iso -tetrahydrocannabinol) have been identified as additional products of intramolecular cyclization. The use of Lewis and protic acids in different solvents has been studied to investigate the possible modulation of the reactivity of CBD (cannabidiol). The complete NMR spectroscopic characterizations of the four isomers are reported. High-performance liquid chromatography analysis and 1 H NMR spectra of the reaction mixture were used to assess the percentage ratio of the compounds formed.

Purpose: This study was performed to assess the accuracy of preoperative cone-beam computed tomography (CBCT), when justified for other reasons, in locating the apical foramen and establishing the working length., Materials and Methods: Six electronic databases were searched for studies on this subject. All studies, of any type, were included if they compared measurements of working length with preoperative CBCT to measurements using an electronic apex locator (EAL) or histological reference standard. Due to the high levels of heterogeneity, an inverse-variance random-effects model was chosen, and weighted mean differences were obtained with 95% confidence intervals and P values., Results: Nine studies were included. Compared to a histological reference standard, CBCT indicated that the apical foramen was on average 0.40 mm coronal of its histological position, with a mean absolute difference of 0.48 mm. Comparisons were also performed to an EAL reference standard, but the conclusions could not be considered robust due to high levels of heterogeneity in the results., Conclusion: A low level of evidence is produced suggesting that preoperative CBCT shows the apical foramen to be on average 0.40 mm coronal to its histological position, with a mean absolute difference of 0.48 mm., Competing Interests: Conflicts of Interest: None, (Copyright © 2020 by Korean Academy of Oral and Maxillofacial Radiology.)

Introduction: This study compared bacterial percolation and sealer penetration of a novel obturation technique with the ones of warm vertical condensation technique., Methods and Materials: A bacterial percolation test was carried out with 80 single rooted human teeth divided into 5 groups; A ( n =20): warm vertical condensation and AH-Plus, B ( n =20): CPoint with AH-Plus, C ( n = 20): CPoint with EndoSequence BC, +ve Control ( n =10): teeth with no canal obturation, -ve Control ( n =10): teeth with no access cavity. The samples were inoculated with a multispecies bacterial incoulum. Bacterial percolation was evaluated by turbidity. Confocal laser scanning microscopy (CLSM) was used to observe the presence of gaps and voids. Further 48 extracted human mandibular single-canal premolars were used to determine the sealer penetration. Slices of the samples were observed by CLSM to evaluate tubules penetration of the sealer. Kaplan Meyer survival, ANOVA one way and Tuckey HSD test and a Wilcoxon signed-rank test were utilised., Results: A Kaplan-Meier test showed no significant difference overall ( P >0.05 ) between groups A, B and C. At 43 days, the group B showed a significantly inferior ability to prevent bacterial passage ( P <0.05). The group C showed a deeper sealer penetration than group A and B with statistically significant differences ( P <0.05) for the total penetration (ANOVA one way and Tukey HSD). A Wilcoxon signed-rank test showed statistically significant differences for the penetration in the middle-and apical third of the 3 groups., Conclusion: Based on this in vitro study, the single polymer-cone obturation technique with a resin based- and bioceramic based-sealer behaved similarly to the warm vertical obturation technique in preventing bacterial passage. The bioceramic sealer showed the deepest penetration but did not fully prevent bacterial leakage., Competing Interests: ‘None declared’.

Background: the aim of this study was to assess the 2-year pulp survival of deep carious lesions in teeth excavated using a self-limiting protocol in a single-blind randomized controlled clinical trial., Methods: At baseline, 101 teeth with deep carious lesions in 86 patients were excavated randomly using self-limiting or control protocols. Standardized clinical examination and periapical radiographs of teeth were performed after 1- and 2-year follow-ups (REC 14/LO/0880)., Results: During the 2-year period of the study, 24 teeth failed (16 and 8 at T12 and T24, respectively). Final analysis shows that 39/63 (61.9%) of teeth were deemed successful (16/33 (48.4%) and 23/30 (76.6%) in the control and experimental groups, respectively with a statistically significant difference (z score = 2.3, p = 0.021). Of teeth with severe and mild symptoms at T0, 42.9% and 36.7% respectively failed at T24 ( p > 0.05). Within the self-limiting group, there was a lower success in premolars compared to molars ( p < 0.05)., Conclusion: after 2 years, there was a statistically significant higher pulp survival rate of teeth with deep carious lesions excavated using self-limiting protocols in patients with reversible pulpitis. Molars showed higher success than premolars in teeth excavated using the self-limiting protocol. There was no statistically significant association between the outcome and the severity of symptoms at T0 (ClinicalTrials.gov NCT03071588).

Purpose: This study compared the antimicrobial efficacy of calcium silicate sealers (BioRoot RCS and Total Fill BC) and conventional sealers (AH Plus and Tubli-seal) against planktonic bacteria and a nutrient-stressed multispecies biofilm., Methods: Antimicrobial properties of freshly mixed sealers were investigated using the direct contact test (DCT) and a nutrient-stressed multispecies biofilm comprised of five endodontic strains. Antimicrobial activity was determined using quantitative viable counts and confocal laser scanning microscopy (CLSM) analysis with live/dead staining. The pH of the sealers was analysed over a period of 28 days in Hanks Balanced Salt Solution (HBSS). Analysis of variance (ANOVA) with Tukey tests and the Kruskal-Wallis test were used for data analysis with a significance of 5%., Results: All endodontic sealers exhibited significant antimicrobial activity against planktonic bacteria ( p < 0.05). BioRoot RCS caused a significant reduction in viable counts of the biofilms compared to AH Plus and the control ( p < 0.05), while no significant difference could be observed compared to TotalFill BC and Tubli-seal ( p > 0.05). CLSM analysis showed that BioRoot RCS and TotalFill BC exhibited significant biofilm inhibition compared to Tubli-seal, AH Plus and the control ( p < 0.05). BioRoot RCS presented with the highest microbial killing, followed by TotalFill BC and Tubli-seal. Alkalizing activity was seen from the onset by BioRoot RCS, TotalFill BC and AH Plus. After 28 days, BioRoot RCS demonstrated the highest pH in HBSS (pH > 12)., Conclusions: Calcium silicate sealers exhibited effective antimicrobial properties. This was demonstrated by superior biofilm inhibition capacity and microbial killing, with strong alkalizing activity compared to epoxy-based and zinc oxide-eugenol-based sealers.

The aza-alkylation reaction at indole's C3 position allows the introduction of a differently substituted aminomethyl group, with the formation of a new stereogenic centre. The reaction involves essentially three different partners: an indole, aldehyde and amine. The formation of the reactive iminium species can be catalyzed by metals, Brønsted acids, Lewis acids or organocatalysts. The stereoselective reaction is feasible with satisfactory outcomes. This review summarizes the recent (2000-2019) meaningful papers in which the in-depth study and exploitation of this reactivity are reported.

Background: The aim of this longitudinal, one-year cohort study was to explore the hypothesis that fluorescence sampling of the root canal space prior to obturation could predict the outcome of root canal treatment (RCT)., Methods: Sixty-five teeth underwent primary RCT and were followed up clinically and radiographically. The outcome was determined radiographically with periapical radiographs (PR) and cone beam computed tomography (CBCT) scans., Results: Success at 12 months was predictable based on the fluorescence score. When the fluorescence score (defined as the percentage of signal over total signal including background) was lower than 67, there was a 4.5 times (Odds ratio (OR) = 0.028; 95% confidence interval (CI): 0.003, 0.291, p = 0.001) greater chance of success (90% overall). When the readings were above this threshold, the success rate was 20%., Conclusion: A chairside sampling method is able to predict the outcome of RCT, through the use of paper point sampling and fluorescence staining. This has reduced the prevalence of persistent infections by guiding the optimum time for obturation. ClinicalTrials.gov trial NCT03660163.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients' group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients' group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.

Background: To assess the change of the Schneider membrane thickness measured by CBCT before and after root canal treatment, retreatment and pulp capping procedures., Methods: This retrospective study was conducted on CBCT scans of a patient population of Guy's Hospital NHS Foundation Trust, London. Three groups of patients were studied: Group 1 consisted of patients referred for primary endodontic treatment; Group 2 for endodontic retreatment; Group 3 for indirect pulp capping procedures (serving as a control group). Follow up scans were carried out 1 year after treatment. Measurements were carried out on CBCT scans and data were analysed statistically by Wilcoxon Signed Rank Test. Linear regression was used to assess predictive parameters for membrane thickness., Results: A statistically significant reduction of the Schneider membrane thickness was observed one year after endodontic treatment and retreatment (P < 0.05) but no significant reduction was observed after pulp capping procedures. Linear regression showed that age and gender were significant predictors influencing the Schneider membrane thickness., Conclusions: Within the limitations of this retrospective study, following root canal treatment and re-treatment a Schneiderian membrane thickness reduction occurred at 1-year follow-up. The removal of odontogenic infection following endodontic treatment may help reducing the thickness of the Schneider membrane.

Background: The objective was to evaluate the efficiency of ProTaper Gold (PTG) and Reciproc Blue (RB) NiTi files in obturation material removal from straight root canals assessed by micro-computed tomography., Methods: Fifty-two anterior human teeth were shaped with a PTG rotary system until F2 (25/.08). Specimens were obturated with a continuous wave of condensation technique. For retreatment, specimens were randomly distributed in two experimental groups: PTG group (F4 file) and RB (R40 file). Micro-CT scans were performed before and after retreatment procedures. The percentage of the remaining obturation material compared to the original volume was calculated, as well as the retreatment time. The presence of separated files was recorded. A descriptive analysis was carried out, and nonparametric tests were employed., Results: The mean percentages of remaining obturation material in the PTG group and the RB group were 4.14 ± 4.30% and 4.18 ± 4.29%, respectively. The mean retreatment times for the PTG and RB groups were 144 ± 51 and 163 ± 88 s, respectively. There were no statistically significant differences, neither in removal efficiency ( p > 0.05) nor in retreatment time ( p > 0.05), between the two groups. The coronal and middle thirds presented significantly more remaining obturation material than the apical third ( p < 0.05). No file separation occurred., Conclusions: ProTaper Gold and Reciproc Blue present with comparable efficiency in removing the obturation material, with a similar mean retreatment time.

4,4-Disubstituted 4 H -isoxazol-5-ones bearing a 1,4-naphthoquinone moiety undergo transformation into different types of benzoindolyl products depending on the different reaction conditions. A decarboxylative ring opening/ring closure promoted by catalytic [Ru( p -cymene) 2 Cl 2 ] 2 yields benzo[ f ]indole-4,9-diones. Alternatively, hydrogenation reactions provide the conversion of 4-(1,4-naphthoquinone)-substituted isoxazol-5-ones to benzo[ g ]indole compounds, with the level of reduction depending on the substituents present on the ring. Starting materials have been easily prepared by the functionalization of isoxazolinones with naphthoquinone under mild conditions.

New luminogens for aggregation-induced emission (AIE), which are characterized by a branched cross-conjugated 2,6-bis(1,2,2-triarylvinyl)pyridine motif, have been synthesized exploiting the one-pot Ti-mediated tetraarylation of 2,6-bis(arylethynyl)pyridines. Thin layer solid-state emitters were prepared by spin-coating of the luminogens, while AIE-colloidal dispersions were investigated in terms of optical density and scattering behaviour. This has given insight into particle size distributions, time evolution of the aggregation and the influence of different functionalization patterns on the luminescence of molecular aggregates. In particular, a combination of extinction spectroscopy and dynamic light scattering is being proposed as a powerful method for investigating the dynamic aggregation process in AIE-type colloids., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Background: The aim of this study was to compare the success rate of root canal treatments undertaken using a calcium silicate root canal sealer in combination with a single cone with non-calcium silicate cement and warm vertical condensation., Methods: 150 necrotic or pulpitic teeth were treated. (REC: 08/H0804/79). Following standardized root canal chemo-debridement. The canals were obturated using warm vertical condensation of gutta-percha and epoxy-based sealer (AH plus) or a calcium silicate sealer (BioRoot TM RCS) with a single cone technique. Follow-up assessment was conducted at 12 months using Cone Beam Computed Tomography (CBCT)., Results: At 1-year recall, 104 teeth were assessed (51 AH plus, 53 BioRoot TM RCS). The success rate using loose criteria for the CBCT images and PA radiographs was respectively 80% and 89% in the AH plus/warm vertical condensation group, 84% and 90% in the BioRoot TM RCS/single cone group. There was no statistically significant difference between the two groups (Fisher exact test p value 0.6099 for the CBCT images)., Conclusion: Within the limitations of this non-randomized trial, a calcium silicate cement in combination with single cone resulted in a similar proportion of successful cases compared to warm vertical condensation and epoxy-based sealer.

The palladium-catalyzed aminoazidation of aminoalkenes yielding azidomethyl-substituted nitrogen-containing heterocycles was developed. The procedure requires oxidative conditions and occurs at room temperature in the presence of hydrogen peroxide and NaN 3 as the azide source. These conditions provide selective exo -cyclization/azidation of the carbon-carbon double bond, furnishing a versatile approach toward five-, six-, and seven-membered heterocyclic rings.

Objective:  The purpose of this research was to investigate the effect per se of two shaping and cleaning techniques on the reduction of an in vitro multispecies biofilm., Materials and Methods:  A total of 39 freshly extracted monoradicular teeth for periodontal reason were decoronated. Roots were sectioned longitudinally. After autoclaving, a specific stressed biofilm was grown on the root halves that were subsequently reassembled in a silicone index. Two treatments ( n = 9 each)-RaCe (Schottlander; Letchworth Garden City, United Kingdom) and ProTaper Gold ( PTG; Dentsply Maillefer, Baillagues, Switzerland)-were tested; three noninstrumented samples served as a control group and three were rinsed with saline. Posttreatment samples were taken at three different levels of the root. Colony-forming units were counted after incubations. Additionally, three treatments ( n = 5 each)-RaCe, PTG, and saline only-were evaluated under a confocal laser scanning microscope (CLSM)., Statistical Analysis:  Statistical analysis was conducted using Tukey's test and analysis of variance to evaluate the post-instrumentation bioburden., Results:  Both instrumentations were able to reduce the biofilm; however, differences were not present between them ( p > 0.05). CLSM showed biofilm killing and disruption through mechanical shaping alone., Conclusions:  Intraradicular biofilm is reduced with mechanical shaping. There was no difference between RaCe and PTG systems in biofilm reduction despite differences in design, file sequence, and rotational speed., Competing Interests: None declared.

Introduction: The purpose of this study was firstly to compare the impact of radiographs, cone-beam computed tomographic (CBCT) imaging, and 3D Endo software (Dentsply Sirona, Ballaigues, Switzerland) on the assessment of root canal anatomy and radiographic quality of endodontic treatment and secondly to assess stress levels in the same cohort of residents performing endodontic treatment., Methods: Sixty patients requiring primary molar endodontic treatment were allocated randomly into 3 groups: group 1 (n = 20), conventional radiographs (periapical radiography [PR]) only; group 2 (n = 20), PR and CBCT imaging; and group 3 (n = 20), PR, CBCT imaging, and 3D Endo software. All treatment was performed using a standardized protocol. Residents completed a questionnaire to assess their stress levels and usefulness of the imaging modality used. The radiographic quality of completed cases was assessed by 2 experienced endodontists who were not involved in the supervision of the cases being assessed., Results: Groups 2 (CBCT imaging) and 3 (PR, CBCT imaging, and 3D Endo) proved significantly better than group 1 (PR) (P < .001) for assessing the number of root canals and anatomy and estimating the working lengths. Group 3 provided a significantly more accurate determination of the working level (P = .002). There were significantly more cases with obturation short of the apex (<2 mm) and voids in group 1 compared with group 3 (P < .05) and a significantly higher number of cases with voids in group 1 compared with group 3 (P < .01). Clinicians found treatment to be moderately or very stressful in 75%, 5%, and 0% in groups 1, 2, and 3, respectively., Conclusions: 3D Endo software followed by CBCT imaging were found to be more desirable for the evaluation of root canal anatomy and working lengths and reducing the residents' stress levels., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

This study aimed at evaluating the microtensile bond strength (MTBS) and fractographic features of dentine-bonded specimens created using universal adhesives applied in etch-and-rinse (ER) or self-etching (SE) mode in combination with modern ion-releasing resin-modified glass-ionomer cement (RMGIC)-based materials after load cycling and artificial saliva aging. Two universal adhesives (FTB: Futurabond M+, VOCO, Germany; SCU: Scotchbond Universal, 3M Oral Care, USA) were used. Composite build-ups were made with conventional nano-filled composite (AURA, SDI, Australia), conventional resin-modified glass ionomer cement (Ionolux VOCO, Germany), or a (RMGIC)-based composite (ACTIVA, Pulpdent, USA). The specimens were divided in three groups and immersed in deionized water for 24 h, load-cycled (350,000 cycles; 3 Hz; 70 N), or load-cycled and cut into matchsticks and finally immersed for 8 months in artificial saliva (AS). The specimens were cut into matchsticks and tested for microtensile bond strength. The results were analyzed statistically using three-way ANOVA and Fisher's LSD post hoc test ( p < 0.05). Fractographic analysis was performed through stereomicroscope and FE-SEM. FTB showed no significant drop in bond strength after aging. Unlike the conventional composite, the two RMGIC-based materials caused no bond strength reduction in SCU after load-cycle aging and after prolonged aging (8 months). The SEM fractographic analysis showed severe degradation, especially with composite applied on dentine bonded with SCU in ER mode; such degradation was less evident with the two GIC-based materials. The dentine-bond longevity may be influenced by the composition rather than the mode of application (ER vs. SE) of the universal adhesives. Moreover, the choice of the restorative material may play an important role on the longevity of the finalrestoration. Indeed, bioactive GIC-based materials may contribute to maintain the bonding performance of simplified universal adhesives over time, especially when these bonding systems are applied in ER mode.

The design and the synthesis of new self-assembling conjugates is reported. The target compounds are characterized by the presence of a self-immolative linker that secures a controlled release induced by lipase cleavage. 4-(1,2-Diphenylbut-1-en-1-yl)aniline is used as a self-assembling inducer and amino-thiocolchicine as prototype of drug. The release of thiocolchicine derivative has been demonstrated in vitro in the presence of porcine pancreatic lipase and Celite-supported lipase. The formation of nanoparticles is confirmed by dynamic light scattering, atomic force microscopy, and fluorescence microscopy. The antiproliferative activity has been proved on two human cancer cell lines., Competing Interests: The authors declare no competing financial interest.

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Following the discovery of a type III allosteric modulator of cyclin-dependent kinase 2 (CDK2) characterized by a hexahydrocyclopenta[c]quinolone scaffold, three different series of its derivatives were synthesized and biologically evaluated. Docking of the synthesized compounds into the allosteric pocket of CDK2 allowed the elucidation of structure-activity relationships (SARs). Moreover, the compounds were tested on the wild-type epidermal growth factor receptor (EGFR) kinase domain (KD) and its clinically relevant T790M/L858R mutant form. Herein we describe the first SAR investigation of allosteric ligands that bind to the type III inhibitor pocket of CDK2 and EGFR-KD. Although the activity of the synthesized inhibitors needs to be improved, the obtained results provide clear-cut indications about pharmacophore requirements and selectivity determinants. Remarkably, this study led to the identification of a selective T790M/L858R EGFR allosteric inhibitor that is inactive toward both wild-type EGFR and CDK2. Finally, docking into the T790M/L858R EGFR-KD led us to hypothesize that the compounds bind to the double-mutant EGFR-KD by adopting a binding mode different from that in CDK2, thus rationalizing the observed selectivity profile., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To report a case of a choroidal metastasis from a non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, which responded to Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI)., Background: First- and second-generation EGFR-TKis have been widely used for advanced NSCLC patients; however, acquired resistance to these inhibitors, as T790M mutation, could be present in resistant cases. Third-generation EGFR-TKis have emerged as potential therapeutics to overcome this resistance., Methods: A 54-year-old lady, affected by pulmonary adenocarcinoma with systemic metastases, was diagnosed with choroidal metastasis and since tumor biopsy was positive for the EGFR-T790M mutation, she was included in ASTRIS study, and she received 80 mg tablet of Osimertinib once a day., Results: After a 2-week course of daily therapy with Osimertinib, the improvement of visual acuity was evident with the marked disappearance of visual field defects. We also report a dramatic anatomical reduction of choroidal mass on fundus examination and SD-OCT. These features remained stable at the 4-month follow-up visit., Conclusion: This report demonstrates that Osimertinib is effective for choroidal metastasis of NSCLC harboring an EGFR-T790M mutation, which has progressed on or after first- or second-generation EGFR-TKI therapy.

Effective management of external cervical resorption (ECR) depends on accurate assessment of the true nature and accessibility of ECR; this has been discussed in part 1 of this 2 part article. This aim of this article was firstly, to review the literature in relation to the management of ECR and secondly, based on the available evidence, describe different strategies for the management of ECR. In cases where ECR is supracrestal, superficial and with limited circumferential spread, a surgical repair without root canal treatment is the preferred approach. With more extensive ECR lesions, vital pulp therapy or root canal treatment may also be indicated. Internal repair is indicated where there is limited resorptive damage to the external aspect of the tooth and/or where an external (surgical) approach is not possible due to the inaccessible nature of subcrestal ECR. In these cases, root canal treatment will also need to be carried out. Intentional reimplantation is indicated in cases where a surgical or internal approach is not practical. An atraumatic extraction technique and short extraoral period followed by 2-week splinting are important prognostic factors. Periodic reviews may be indicated in cases where active management is not pragmatic. Finally, extraction of the affected tooth may be the only option in untreatable cases where there are aesthetic, functional and/or symptomatic issues., (© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

A single-blind randomized controlled clinical trial in patients with deep caries and symptoms of reversible pulpitis compared outcomes from a self-limiting excavation protocol using chemomechanical Carisolv gel/operating microscope (self-limiting) versus selective removal to leathery dentin using rotary burs (control). This was followed by pulp protection with mineral trioxide aggregate (MTA) and restoration with glass ionomer cement and resin composite, all in a single visit. The pulp sensibility and periapical health of teeth were assessed after 12 mo, in addition to the differences in bacterial tissue concentration postexcavation. Apical radiolucencies were assessed using cone beam computed tomography/periapical radiographs (CBCT/PAs) taken at baseline 0 mo (M0) and 12 mo (M12). In total, 101 restorations in 86 patients were placed and paired subsurface, and deep (postexcavation) dentin samples were obtained. DNA was extracted and bacteria-specific 16S ribosomal RNA gene quantitative polymerase chain reaction was performed. No significant difference was found in bacterial copy numbers normalized to mass of dentin ("bacterial tissue concentration") between the self-limiting (96.3% reduction) and control protocols (97.1%, P = 0.33). The probability of 12-mo success was 4 times (odds ratio [OR] = 4.33; confidence interval [CI], 1.2-15.6; P = 0.025) higher in the self-limiting protocol compared to the control (conventional excavation technique), with pulp survival rates of 73.3% and 90%, respectively ( P = 0.049). Molars had a 4 times higher probability of success compared to premolars (OR, 4.17; CI, 1.17-14.9; P = 0.028), and symptom severity did not statistically predict outcome (OR, 0.41; CI, 0.12-13.9, P = 0.153). CBCT detected significantly more periapical (PA) lesions than PA radiographs at the baseline visit ( P < 0.001). In conclusion, the self-limiting caries excavation protocol under magnification increased pulp survival rate compared to rotary bur excavation ( ClinicalTrials.gov NCT03071588).