[Development of the EULAT eCollect application for electronic data collection within the European-Latin American consortium towards eradication of preventable gallbladder cancer - EULAT Eradicate GBC]. / Desarrollo de la aplicación EULAT eCollect para el registro electrónico de datos del Consorcio Europeo-Latinoamericano contra el Cáncer de Vesícula Biliar-EULAT Eradicate GBC.

The European-Latin American Consortium towards Eradication of Preventable Gallbladder Cancer (GBC) - EULAT Eradicate CVB is collecting high-quality data and samples in four Latin American countries with a high incidence of GBC: Argentina, Bolivia, Chile and Peru. The goal is to build a unique biorepository integrated with a customized informatics platform, identify, validate, and functionally characterize novel GBC risk biomarkers, and develop GBC prediction models integrating epidemiological and genetic-molecular risk factors. We decided to develop the electronic data collection application EULAT eCollect to facilitate the retrieval of socio-demographic, clinical, lifestyle, nutritional, and sample information from the 15,000 Latin Americans we are enrolling. The EULAT eCollect app reduces the time spent by study participants, limits the use of paper and ink, minimizes the costs and errors associated with completing written forms and their subsequent digitization, and allows close monitoring of local recruitment rates and data quality. We describe in this article the design and implementation of EULAT eCollect, which started with the specification of functional and non-functional requirements and ended with the implementation and subsequent validation of the four application modules: I Socio-demographic interview, II Sample information, III Case report form, and IV Food frequency questionnaire. We present both general and technical results and our experience with the Open Data Kit software, which may be of interest for future research projects, especially those on personalized cancer prevention conducted in low- and middle-income regions.

Immediate loading of dental implants in edentulous mandibles using Locator attachments or Dolder bars: A 9-year prospective randomized clinical study.

AIM: To evaluate the long-term survival, incidence of prosthetic/technical and biological complications and the oral-health-related quality of life in patients with an edentulous mandible who were fitted with overdentures on two immediately loaded implants in the symphyseal area. MATERIALS AND METHODS: Forty-six patients with edentulous mandibles received two immediately loaded implant-retained dentures with either two Locator attachments or egg-shaped bar attachments. Implant outcomes were recorded after a period of observation of 9 years and included prosthetic complications, modified gingiva index (mGI), modified plaque index (mPI), oral health impact profile (OHIP-G) and radiographic estimation of bone loss. RESULTS: In 2020/2021, 27 patients with 54 implants were still available for follow-up. In total, nine implants in six patients were lost. Survival was 89.1% in the bar group and 91.3% in the Locator group. Implant success was 84.6% in the Locator group and 76.9% in the bar group. The mPI values were significantly higher in the bar group than in the Locator group, whereas no difference was seen in the mGI values. During the observation period, 152 prosthetic complications occurred, but the OHIP-G score did not differ significantly. CONCLUSIONS: There was no difference in implant survival between Locator or joint bar attachments over a 9-year observation period. Joint bar attachments were associated with slightly more complications, while patients in the Locator group were able to maintain better oral hygiene. The study was registered in the German Register of Clinical (Trials DRKS00004245).

Early failures when using three different adhesively retained core build-up materials-a randomized controlled trial.

OBJECTIVES: To compare the failure rates for three different adhesively retained core build-up composites up to the incorporation of a permanent fixed dental prosthesis (FDP), and to identify potential failure risk factors. MATERIAL AND METHODS: A randomized controlled trial of 300 participants in need of a core build-up to restore a vital abutment tooth before prosthetic treatment was conducted. Participants were assigned by stratified block randomization to one of three study groups: Rebilda DC (RDC), Clearfil DC Core (CDC), or Multicore Flow (MF). Test teeth were prepared by use of the respective manufacturer's adhesive system. The total-etch technique was used for RDC and MF, and the self-etch technique for CDC. Participants were treated by dentists (n = 150) or dental students (n = 150). Failure rates of core build-ups before incorporation of FDPs were investigated using univariate and multiple logistic regression. RESULTS: The overall failure rate was 8% (n = 23). Rate differences between the three investigated groups did not reach statistical significance (p > 0.05). The mean time between placement of core build-ups and placement of fixed dental prostheses was 12.2 (SD: 14.2) weeks. Conversely, larger cavities (> 3 surfaces) and treatment by dental students were independently associated with an increased failure risk (p < 0.05). CONCLUSIONS: The main risk factors for early failure seem to be the size of the core build-up and clinical experience of the operator, whereas failure rates of core build-up materials combined with a self-etch approach seem to be similar to the rates of materials combined with the total-etch technique. CLINICAL SIGNIFICANCE: This research article should give clinicians an impression of the short-term performance of different adhesively retained core build-ups using different adhesive techniques/materials. Moreover, predominant influencing factors for the success or failure should be pictured.

Clinical Performance of Posterior Inlay-Retained and Wing-Retained Monolithic Zirconia Resin-Bonded Fixed Partial Dentures: Stage One Results of a Randomized Controlled Trial.

PURPOSE: To prospectively compare the clinical performance of posterior inlay-retained and wing-retained monolithic zirconia fixed partial dentures (FPDs). MATERIALS AND METHODS: After simple randomization, 30 participants received either one inlay-retained (n = 15; mean age: 56.38 ± 12.70 years; 10 men [66.7%]) or one wing-retained (n = 15; mean age: 45.90 ±13.24 years; 7 men [46.7%]) FPD. The restorations, which predominantly replaced first molars, were fabricated from translucent, 3 mol% yttria-stabilized zirconia and attached with self-etching resin cement. Restorations and abutment teeth were clinically followed up for complications one week and 3, 6, and 12 months after cementation. Plaque and gingival scores, probing pocket depths, and attachment levels were recorded for the abutment and contralateral reference teeth both before treatment and during follow-up examinations. The restorations were also assessed in accordance with FDI World Dental Federation criteria. Statistical analyses were conducted with R (α = 0.05). An adaptive, 2-stage study design based on the incidence of failure-free survival in the groups after 12 months (stage 1) was implemented. Predefined decision rules were used to determine whether further recruitment (stage 2) would enable the detection of a statistically significant difference between the restoration designs with sufficient power. RESULTS: During 12 months, only one wing retainer debonded which required removal of the FPD. Failure-free survival was thus 93.3% for wing-retained and 100% for inlay-retained FPDs (log-rank test, p = 0.317). Moderate aftercare resulted in intervention-free rates of 78.8% and 86.7% for inlay-retained and wing-retained restorations, respectively (log-rank test, p = 0.605). Based on FDI World Dental Federation criteria, all restorations were acceptable at the 12-month follow-up (Fisher-Boschloo test, p = 0.161). Plaque, gingival, and periodontal scores remained practically unchanged from before treatment to the 12-month follow-up. Recruitment was stopped after stage 1 because, based on the small difference in the incidence of failure-free survival in the groups, it was accepted that it would not be possible to recruit the necessary number of participants to show a statistically significant difference between the retainer designs. CONCLUSIONS: Both inlay-retained and wing-retained monolithic zirconia resin-bonded FPDs performed well for the 12-month, short-term follow-up period.

PRDM15 Is Associated with Risk of Chronic Obstructive Pulmonary Disease in a Rural Population in Chile.

BACKGROUND: Genome-wide association studies (GWAS) have accelerated our understanding of the genetic underpinnings of chronic obstructive pulmonary disease (COPD); however, GWAS populations have typically consisted of European descent, with ∼1% of Latin American ancestry. OBJECTIVE: To overcome this limitation, we conducted a GWAS in a rural Chilean population with increased COPD risk to investigate genetic variation of COPD risk in this understudied minority population. METHOD: We carried out a case-control study of 214 COPD patients (defined by the GOLD criteria) and 193 healthy controls in Talca, Chile. DNA was extracted from venous blood and genotyped on the Illumina Global Screening Array (n = 754,159 markers). After exclusion based on Hardy-Weinberg equilibrium (p ≤ 0.001), call rates (<95%), and minor allele frequencies (<0.5%) in controls, 455,564 markers were available for logistic regression. RESULTS: PRDM15 rs1054761 C allele (p = 2.22 × 10-7) was associated with decreased COPD risk. Three PRDM15 SNPs located on chromosome 21 were significantly associated with COPD risk (p < 10-6). Two of these SNPs, rs1054761 and rs4075967, were located on a noncoding transcript variant region of the gene. CONCLUSION: PRDM15 overexpression may play a role in the B-cell dysregulation in COPD pathogenesis. To the best of our knowledge, the association between PRDM15 and COPD risk was not previously found in GWAS studies in largely European populations, highlighting the importance of investigating novel variants associated with COPD risk among ethnically diverse populations.

Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy.

Cardiovascular disease (CVD) is the leading cause of increased mortality in patients with CKD and is further aggravated by peritoneal dialysis (PD). Children are devoid of preexisting CVD and provide unique insight into specific uremia- and PD-induced pathomechanisms of CVD. We obtained peritoneal specimens from children with stage 5 CKD at time of PD catheter insertion (CKD5 group), children with established PD (PD group), and age-matched nonuremic controls (n=6/group). We microdissected omental arterioles from tissue layers not directly exposed to PD fluid and used adjacent sections of four arterioles per patient for transcriptomic and proteomic analyses. Findings were validated in omental and parietal arterioles from independent pediatric control (n=5), CKD5 (n=15), and PD (n=15) cohorts. Transcriptomic analysis revealed differential gene expression in control versus CKD5 arterioles and in CKD5 versus PD arterioles. Gene ontology analyses revealed activation of metabolic processes in CKD5 arterioles and of inflammatory, immunologic, and stress-response cascades in PD arterioles. PD arterioles exhibited particular upregulation of the complement system and respective regulatory pathways, with concordant findings at the proteomic level. In the validation cohorts, PD specimens had the highest abundance of omental and parietal arteriolar C1q, C3d, terminal complement complex, and phosphorylated SMAD2/3, a downstream effector of TGF-ß Furthermore, in the PD parietal arterioles, C1q and terminal complement complex abundance correlated with the level of dialytic glucose exposure, abundance of phosphorylated SMAD2/3, and degree of vasculopathy. We conclude that PD fluids activate arteriolar complement and TGF-ß signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.

Tailored selection of study individuals to be sequenced in order to improve the accuracy of genotype imputation.

The addition of sequence data from own-study individuals to genotypes from external data repositories, for example, the HapMap, has been shown to improve the accuracy of imputed genotypes. Early approaches for reference panel selection favored individuals who best reflect recombination patterns in the study population. By contrast, a maximization of genetic diversity in the reference panel has been recently proposed. We investigate here a novel strategy to select individuals for sequencing that relies on the characterization of the ancestral kernel of the study population. The simulated study scenarios consisted of several combinations of subpopulations from HapMap. HapMap individuals who did not belong to the study population constituted an external reference panel which was complemented with the sequences of study individuals selected according to different strategies. In addition to a random choice, individuals with the largest statistical depth according to the first genetic principal components were selected. In all simulated scenarios the integration of sequences from own-study individuals increased imputation accuracy. The selection of individuals based on the statistical depth resulted in the highest imputation accuracy for European and Asian study scenarios, whereas random selection performed best for an African-study scenario. Present findings indicate that there is no universal 'best strategy' to select individuals for sequencing. We propose to use the methodology described in the manuscript to assess the advantage of focusing on the ancestral kernel under own study characteristics (study size, genetic diversity, availability and properties of external reference panels, frequency of imputed variants…).

Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients.

BACKGROUND: To date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma. METHODS: Survival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0. RESULTS: In recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95% CI = 0.26-0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46% of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45%). Severe side effects CTCAE III/IV were observed in 9% of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation. CONCLUSION: In this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation.

High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients.

BACKGROUND: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient's family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. METHODS: Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. RESULTS: Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P < 0.0001). 1 % of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14 % vs. 5 %, P = 0.03), 2) diagnosed at early-age irrespective of family history (28 % vs. 11 %, P = 0.0003), 3) had a family history of breast cancer (49 % vs. 12 %, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81 % vs. 28 %, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22-53) vs. 28 years (range 18-67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95 % CI 2.50-7.14; P < 0.0001). CONCLUSION: Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC.

Local and global ancestry inference and applications to genetic association analysis for admixed populations.

Genetic association studies in recently admixed populations offer exciting opportunities to identify novel variants underlying phenotypic diversity. At the same time, genetic heterogeneity resulting from population admixture has to be accounted for to ensure validity of association tests. The whole-genome sequence data and the genome-wide single-nucleotide polymorphism chip data for Mexican American individuals provided by Genetic Analysis Workshop 18 (GAW18) presents a unique opportunity to evaluate and compare methods for the statistical analysis of admixed genetic data. We summarize here the five contributions from the GAW18 working group on admixture mapping and adjusting for admixture. Although group members considered a variety of research topics, the general theme was inference and consideration of ancestry admixture in genetic analyses. The topics considered can be grouped into three categories: (1) global and local ancestry inference and estimation, (2) association and admixture mapping, and (3) genotype imputation in admixed samples. We describe the approaches that were used and the most relevant findings from each contribution. We also provide insight into the strengths and limitations of the state-of-the-art methods considered for genetic analyses in admixed populations.

Methylation status of HPV16 E2-binding sites classifies subtypes of HPV-associated oropharyngeal cancers.

BACKGROUND: The human papillomavirus (HPV) E2 protein is a transcriptional repressor of the oncogenes E6/E7 and loss of E2 function is considered a key step in carcinogenesis. Integration of HPV into the host genome may disrupt the E2 gene. Furthermore, methylation of CpG dinucleotides in E2-binding sites (E2BSs) in the HPV upstream regulatory region may interfere with transcriptional repression of E6 and E7 by E2. The authors hypothesized that the CpG methylation status of E2BS identifies subtypes of HPV type 16 (HPV16)-associated oropharyngeal squamous cell cancers (OPSCC) in association with E2 gene integrity and viral integration. METHODS: Methylation of 10 CpG dinucleotides within the upstream regulatory region, encompassing E2BSs 1, 2, 3, and 4, was quantitatively analyzed by bisulfite pyrosequencing in 57 HPV16-associated OPSCC cases. E2 status was analyzed by gene amplification and quantitative real-time reverse transcriptase-polymerase chain reaction. Viral integration was determined by integration-specific polymerase chain reaction methods. RESULTS: Three subgroups with differential methylation at E2BS3 and E2BS 4 were identified: 1) complete methylation (>80%) associated with the presence of integrated HPV genomes with an intact E2 gene; 2) intermediate methylation levels (20%-80%) with predominantly episomal HPV genomes with intact E2; and 3) no methylation (<20%) with a disrupted E2 gene. Patients with high methylation levels tended to have a worse 5-year overall survival compared with patients with intermediate methylation (hazard ratio, 3.23; 95% confidence interval, 1.13-9.24 [P = .06]). CONCLUSIONS: Methylation of E2BS3 and E2BS4 in OPSCC is associated with E2 integrity and viral physical status. It might explain deregulated viral oncogene expression in the presence of E2. The prognostic significance of E2BS methylation for patients with HPV-associated OPSCC needs to be analyzed further.

EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma.

UNLABELLED: Mouse Double Minute homolog 4 (MDM4) gene up-regulation often occurs in human hepatocellular carcinoma (HCC), but the molecular mechanisms responsible for its induction remain poorly understood. Here we investigated the role of the phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin (PI3K/AKT/mTOR) axis in the regulation of MDM4 levels in HCC. The activity of MDM4 and the PI3K/AKT/mTOR pathway was modulated in human HCC cell lines by way of silencing and overexpression experiments. Expression of main pathway components was analyzed in an AKT mouse model and human HCCs. MDM4 inhibition resulted in growth restraint of HCC cell lines both in vitro and in vivo. Inhibition of the PI3K-AKT and/or mTOR pathways lowered MDM4 protein levels in HCC cells and reactivated p53-dependent transcription. Deubiquitination by ubiquitin-specific protease 2a and AKT-mediated phosphorylation protected MDM4 from proteasomal degradation and increased its protein stability. The eukaryotic elongation factor 1A2 (EEF1A2) was identified as an upstream inducer of PI3K supporting MDM4 stabilization. Also, we detected MDM4 protein up-regulation in an AKT mouse model and a strong correlation between the expression of EEF1A2, activated/phosphorylated AKT, and MDM4 in human HCC (each rho > 0.8, P < 0.001). Noticeably, a strong activation of this cascade was associated with shorter patient survival. CONCLUSION: The EEF1A2/PI3K/AKT/mTOR axis promotes the protumorigenic stabilization of the MDM4 protooncogene in human HCC by way of a posttranscriptional mechanism. The activation level of the EEF1A2/PI3K/AKT/mTOR/MDM4 axis significantly influences the survival probability of HCC patients in vivo and may thus represent a promising molecular target.

Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma.

UNLABELLED: The far upstream element binding protein (FBP) and the FBP-interacting repressor (FIR) represent molecular tools for transcriptional fine tuning of target genes. Strong overexpression of FBP in human hepatocellular carcinoma (HCC) supports tumor growth and correlates with poor patient prognosis. However, the role of the transcriptional repressor FIR in hepatocarcinogenesis remains poorly delineated. We show that overexpression of FIR correlates with tumor dedifferentiation and tumor cell proliferation in about 60% of primary HCCs. Elevated FIR levels are associated with genomic gains of the FIR gene locus at chromosome 8q24.3 in human HCC specimens. In vitro, nuclear enrichment of FIR supports HCC cell proliferation and migration. Expression profiling of HCC cells after small interfering RNA (siRNA)-mediated silencing of FIR identified the transcription factor DP-1 (TFDP1) as a transcriptional target of FIR. Surprisingly, FIR stimulates the expression of FBP in a TFDP1/E2F1-dependent manner. FIR splice variants lacking or containing exon 2 and/or exon 5 are expressed in the majority of HCCs but not in normal hepatocytes. Specific inhibition of FIR isoforms with and without exon 2 revealed that both groups of FIR splice variants facilitate tumor-supporting effects. This finding was confirmed in xenograft transplantation experiments with lentiviral-infected short hairpin RNA (shRNA) targeting all FIR variants as well as FIR with and without exon 2. CONCLUSION: High-level nuclear FIR does not facilitate repressor properties but supports tumor growth in HCC cells. Thus, the pharmacological inhibition of FIR might represent a promising therapeutic strategy for HCC patients with elevated FIR expression.

Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer.

UNLABELLED: Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-α1 (imp-α1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-α1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P<0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp-α1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp-α1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. CONCLUSION: The CAS/imp-α1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-α1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis.

Electroplated and cast double crown-retained removable dental prostheses: 6-year results from a randomized clinical trial.

OBJECTIVES: The purpose of this study was to evaluate the clinical performance of removable dental prostheses (RDP) supported by either electroplated (EP-RDP) or cast (C-RDP) double crowns. MATERIAL AND METHODS: Fifty-four participants received a total of 60 RDP. Two hundred and seventeen abutment teeth were provided with double crowns. The participants were randomly assigned to two groups (EP-RDP or C-RDP). Re-evaluations took place after 6 months and then once a year up to 6 years. Primary endpoint was survival time for RDP and abutment teeth; secondary endpoints were failure of facing, decementation of primary crown, and post-prosthetic endodontic treatment. T, U, and chi-squared tests were used to assess the homogeneity of the EP-RDP and C-RDP groups. Survival differences were analyzed with log-rank tests and Cox regression models; secondary endpoints were assessed by the use of logistic regression. RESULTS: Six-year survival was 77 % for EP-RDP and 97 % for C-RDP. Cumulative survival of abutment teeth was 85 % for EP-RDP and 91 % for C-RDP; differences between survivals in the two groups did not reach statistical significance. Survival of abutment teeth depended on tooth vitality. Failures of facings, decementations, or post-prosthetic endodontic treatments were not different between groups. CONCLUSIONS: To identify possible differences between different double crown systems, longer follow-up periods and/or larger numbers of patients are needed. CLINICAL RELEVANCE: Survival of teeth supporting double crown-retained RDP is affected by their vitality. Clinical performance was acceptable for both RDP supported by electroplated or cast double crowns.

Efficacy and nontarget effects of transarterial chemoembolization in bridging of hepatocellular carcinoma patients to liver transplantation: a histopathologic study.

PURPOSE: To histologically evaluate the efficacy and nontarget effects induced by transarterial chemoembolization as a "bridge" treatment of hepatocellular carcinoma (HCC) before liver transplantation (LT) and its relation to patient survival. MATERIALS AND METHODS: Between October 2003 and January 2011, 51 patients with HCC underwent LT after chemoembolization with iodized oil, small spherical particles, and carboplatin. The decision for LT was made according to national guidelines. The efficacy and nontarget effects of chemoembolization were determined histologically in explanted livers, and their impact on patients' survival after LT was analyzed. RESULTS: A total of 126 chemoembolization procedures were performed in 51 patients; the median number of procedures per patient was three (range, one to six). The extent of HCC necrosis was less than or equal to 50% in 32% of treated HCCs, more than 50% and less than or equal to 90% in 17%, and more than 90%-99% in 14%; 38% showed complete necrosis of the lesion. The most common nontarget effects were focal necrosis of the liver parenchyma adjacent to the embolized HCC nodule (28%), intralesional (micro)abscess (26%), intralesional hemorrhage (22%), and peritumoral bile duct necrosis (12%). Based on histopathologic examination, 35% of patients had HCC that did not meet Milan criteria. None of these findings was significantly associated with patient survival after LT. CONCLUSIONS: Transarterial chemoembolization induces histopathologically confirmed HCC necrosis with a high degree of efficacy, but histologically proven complete HCC necrosis was not predictive of survival in this cohort of patients. Although histopathologic examination revealed (clinically relevant) nontarget effects in a subset of patients, they did not impair survival.

A randomized controlled phase IIb wound healing trial of cutaneous leishmaniasis ulcers with 0.045% pharmaceutical chlorite (DAC N-055) with and without bipolar high frequency electro-cauterization versus intralesional antimony in Afghanistan.

BACKGROUND: A previously published proof of principle phase IIa trial with 113 patients from Kabul showed that bipolar high-frequency (HF) electro-cauterization (EC) of cutaneous leishmaniasis (CL) ulcers and subsequent moist wound treatment (MWT) closed 85% of all Leishmania (L.) tropica lesions within 60 days. METHODS: A three-armed phase IIb, randomized and controlled clinical trial was performed in Mazar-e-Sharif. L. tropica- or L. major-infected CL patients received intradermal sodium stibogluconate (SSG) (Group I); HF-EC followed by MWT with 0.045% DAC N-055 (Group II); or MWT with 0.045% DAC N-055 in basic crème alone (Group III). The primary outcome was complete epithelialisation before day 75 after treatment start. RESULTS: 87 patients enrolled in the trial were randomized into group I (n = 24), II (n = 32) and III (n = 31). The per-protocol analysis of 69 (79%) patients revealed complete epithelialisation before day 75 in 15 (of 23; 65%) patients of Group I, in 23 (of 23; 100%) patients of Group II, and in 20 (of 23; 87%) patients of Group III (p = 0.004, Fisher's Exact Test). In the per-protocol analysis, wound closure times were significantly different between all regimens in a pair-wise comparison (p = 0.000039, Log-Rank (Mantel-Cox) test). In the intention-to-treat analysis wound survival times in Group II were significantly different from those in Group I (p = 0.000040, Log-Rank (Mantel-Cox) test). Re-ulcerations occurred in four (17%), three (13%) and seven (30%) patients of Group I, II or III, respectively (p = 0.312, Pearson Chi-Square Test). CONCLUSIONS: Treatment of CL ulcers with bipolar HF-EC followed by MWT with 0.045% DAC N-055 or with DAC N-055 alone showed shorter wound closure times than with the standard SSG therapy. The results merit further exploration in larger trials in the light of our current knowledge of in vitro and in vivo activities of chlorite. Clinicaltrials.gov ID: NCT00996463. Registered: 15th October 2009.

Performance evaluation of a health insurance in Nigeria using optimal resource use: health care providers perspectives.

BACKGROUND: Performance measures are often neglected during the transition period of national health insurance scheme implementation in many low and middle income countries. These measurements evaluate the extent to which various aspects of the schemes meet their key objectives. This study assesses the implementation of a health insurance scheme using optimal resource use domains and examines possible factors that influence each domain, according to providers' perspectives. METHODS: A retrospective, cross-sectional survey was done between August and December 2010 in Kaduna state, and 466 health care provider personnel were interviewed. Optimal-resource-use was defined in four domains: provider payment mechanism (capitation and fee-for-service payment methods), benefit package, administrative efficiency, and active monitoring mechanism. Logistic regression analysis was used to identify provider factors that may influence each domain. RESULTS: In the provider payment mechanism domain, capitation payment method (95%) performed better than fee-for-service payment method (62%). Benefit package domain performed strongly (97%), while active monitoring mechanism performed weakly (37%). In the administrative efficiency domain, both promptness of referral system (80%) and prompt arrival of funds (93%) performed well. At the individual level, providers with fewer enrolees encountered difficulties with reimbursement. Other factors significantly influenced each of the optimal-resource-use domains. CONCLUSIONS: Fee-for-service payment method and claims review, in the provider payment and active monitoring mechanisms, respectively, performed weakly according to the providers' (at individual-level) perspectives. A short-fall on the supply-side of health insurance could lead to a direct or indirect adverse effect on the demand-side of the scheme. Capitation payment per enrolees should be revised to conform to economic circumstances. Performance indicators and providers' characteristics and experiences associated with resource use can assist policy makers to monitor and evaluate health insurance implementation.

Variants at chromosome 20 (ASIP locus) and melanoma risk.

Agouti signaling protein (ASIP) locus on chromosome 20q11 is implicated, as shown by genome-wide association studies, in phenotype variation and melanoma risk. We genotyped 837 melanoma cases and 1,154 controls for 21 single nucleotide polymorphisms (SNPs) informative for 495 polymorphisms at the locus. Our data showed an increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03-1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. The main effect of rs4911414, as reported previously, was in tandem with a 10 kb adjacent polymorphism rs1015362; two constituted risk-associated haplotype/diplotype. Except for rs1015363, none of the 12 tagging SNPs, genotyped to cover 239.9 kb region with polymorphisms linked to rs4911414 and rs1015362, were associated with melanoma. Our data confirmed a previous association of melanoma risk (OR 1.82, 95% CI 1.37-2.41) with rs4911442, located in intron 5 of the nuclear receptor coactivator 6 (NCOA6) gene. The rs910871, one of the six variants, genotyped to cover NCOA6, showed an association with melanoma risk (OR 1.33, 95% CI 1.04-1.70). Both, rs4911442 and rs910871 were in moderate linkage with a, previously reported, risk-associated rs910873 polymorphism. A haplotype from the variants within NCOA6 showed an association with risk of melanoma (OR 1.49, 95% CI 1.17-1.88). Interaction between risk-associated polymorphisms and previously genotyped melanocortin receptor 1 (MC1R) variants, in our study, was not statistically significant. Nevertheless, the carriers of the variant alleles over the background of MC1R variants were at a higher risk than the carriers not enriched for MC1R variants. Our data confirmed the association of different variants at chromosome 20q11 with melanoma risk.

Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population-based GENICA study and external genetic databases.

Small ubiquitin-like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently USPL1 (ubiquitin-specific peptidase-like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population-based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30-0.81). Case-only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39-0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.