Bonferroni-adjusted Significance Level Research Articles

A novel injectable boron doped-mesoporous nano bioactive glass loaded-alginate composite hydrogel as a pulpotomy filling biomaterial for dentin regeneration

BackgroundDifferent materials have been used as wound dressings after vital pulp therapies. Some of them have limitations such as delayed setting, difficult administration, slight degree of cytotoxicity, crown discoloration and high cost. Therefore, to overcome these disadvantages, composite scaffolds have been used in regenerative dentistry. This study aims to construct and characterize the physicochemical behavior of a novel injectable alginate hydrogel loaded with different bioactive glass nanoparticles in various concentrations as a regenerative pulpotomy filling material.MethodsAlginate hydrogels were prepared by dissolving alginate powder in alcoholic distilled water containing mesoporous bioactive glass nanoparticles (MBG NPs) or boron-doped MBG NPs (BMBG NPs) at 10 and 20 wt% concentrations. The mixture was stirred and incubated overnight in a water bath at 50 0 C to ensure complete solubility. A sterile dual-syringe system was used to mix the alginate solution with 20 wt% calcium chloride solution, forming the hydrogel upon extrusion. Then, constructed hydrogel specimens from all groups were characterized by FTIR, SEM, water uptake percentage (WA%), bioactivity and ion release, and cytotoxicity. Statistical analysis was done using One-Way ANOVA test for comparisons between groups, followed by multiple pairwise comparisons using Bonferroni adjusted significance level (p < 0.05).ResultsAlginate/BMBG loaded groups exhibited remarkable increase in porosity and pore size diameter [IIB1 (168), IIB2 (183) (µm)]. Similarly, WA% increased (~ 800%) which was statistically significant (p < 0.05). Alginate/BMBG loaded groups exhibited the strongest bioactive capability displaying prominent clusters of hydroxyapatite precipitates on hydrogel surfaces. Ca/P ratio of precipitates in IIA2 and IIB1 (1.6) were like Ca/P ratio for stoichiometric pure hydroxyapatite (1.67). MTT assay data revealed that the cell viability % of human gingival fibroblast cells have declined with increasing the concentration of both powders and hydrogel extracts in all groups after 24 and 48 h but still higher than the accepted cell viability % of (˃70%).ConclusionsThe outstanding laboratory performance of the injectable alginate/BMBGNPs (20 wt%) composite hydrogel suggested it as promising candidate for pulpotomy filling material potentially enhancing dentin regeneration in clinical applications.

Meta-analysis identifies key genes and pathways implicated in Benzo[a]pyrene exposure response

IntroductionBenzo[a]pyrene (B[a]P) is a carcinogenic polycyclic aromatic hydrocarbon that poses significant risks to human health. B[a]P influences cellular processes via intricate interactions; however, a comprehensive understanding of B[a]P's effects on the transcriptome remains elusive. This study aimed to conduct a comprehensive analysis focused on identifying relevant genes and signaling pathways affected by B[a]P exposure and their impact on human gene expression. MethodsWe searched the Gene Expression Omnibus database and identified four studies involving B[a]P exposure in human cells (T lymphocytes, hepatocellular carcinoma cells, and C3A cells). We utilized two approaches for differential expression analysis: the LIMMA package and linear regression. A meta-analysis was utilized to combine log fold changes (FC) and p-values from the identified studies using a random effects model. We identified significant genes at a Bonferroni-adjusted significance level of 0.05 and determined overlapping genes across datasets. Pathway enrichment analysis elucidated key cellular processes modulated by B[a]P exposure. ResultsThe meta-analysis revealed significant upregulation of CYP1B1 (log FC = 1.15, 95% CI: 0.51–1.79, P < 0.05, I2 = 82%) and ASB2 (log FC = 0.44, 95% CI: 0.20–0.67, P < 0.05, I2 = 40%) in response to B[a]P exposure. Pathway analyses identified 26 significantly regulated pathways, with the top including Aryl Hydrocarbon Receptor Signaling (P = 0.00214) and Xenobiotic Metabolism Signaling (P = 0.00550). Key genes CYP1A1, CYP1B1, and CDKN1A were implicated in multiple pathways, highlighting their roles in xenobiotic metabolism, oxidative stress response, and cell cycle regulation. ConclusionThe results provided insights into the mechanisms of B[a]P toxicity, highlighting CYP1B1's key role in B[a]P bioactivation. The findings underscored the complexity of B[a]P's mechanisms of action and their potential implications for human health. The identified genes and pathways provided a foundation for further exploration and enhanced our understanding of the multifaceted biological activities associated with B[a]P exposure.

Quantitative assessment of brown adipose tissue whitening in a high-fat-diet murine model using synthetic magnetic resonance imaging

PurposeThis study aimed to quantitatively evaluate the whitening process of brown adipose tissue (BAT) in mice using synthetic magnetic resonance imaging (SyMRI) and analyzed the correlation between SyMRI quantitative measurements of BAT and serum lipid profiles. MethodsFifteen C57BL/6 mice were divided into three groups and fed different diets as follows: normal chow diet for 12 weeks, NCD group; high-fat diet (HFD) for 12 weeks, HFD-12w group; and HFD for 36 weeks, HFD-36w group. Mice were scanned using 3.0 T SyMRI. T1 and T2 values of BAT and interscapular BAT (iBAT) volume were measured. After sacrifice, the body weight of mice, lipid profiles, BAT morphology, and uncoupling protein 1 (UCP1) levels were determined. Statistical analysis was performed using one-way analysis of variance or Kruskal–Wallis test followed by Bonferroni correction for pairwise comparisons. Bonferroni-adjusted significance level was set at P < 0.017 (alpha: 0.05/3 = 0.017). ResultsT2 values of BAT in the HFD-12w group were significantly higher than those in the NCD group (P < 0.001), and those in the HFD-36w group were significantly higher than those in the other two groups (both P < 0.001). The iBAT volume in the HFD-36w group was significantly higher than that in the HFD-12w (P = 0.013) and NCD groups (P = 0.005). T2 values of BAT and iBAT volume were significantly correlated with serum lipid profiles and mouse body weight. ConclusionsSyMRI can noninvasively evaluate the whitening process of BAT using T2 values and iBAT volume, thereby facilitating the visualization of the whitening process.

Genetic Evidence for the Causal Association of Circulating Cytokines and Growth Factors With Coronary Artery Disease.

Observational studies have suggested the potential role of inflammatory factors in the risk of coronary artery disease (CAD). We aimed to perform 2-sample Mendelian randomization (MR) analyses to assess the causal association between circulating cytokines/growth factors and CAD. The instrumental variables for 28 circulating cytokines and growth factors were identified from a genome-wide association study of 8293 European participants. Summary-level data on CAD were derived from a large genome-wide association study (71 602 cases and 260 875 controls). We used the inverse-variance-weighted and Wald ratio methods as our main MR methods. The weighted median, simple median, maximum likelihood, MR pleiotropy residual sum and outlier, and MR-Egger methods were performed as sensitivity analyses. Genetic colocalization analyses were conducted to validate the robustness of our MR findings. We found that genetically predicted circulating levels of macrophage migration inhibitory factor were associated with an increased risk of CAD at the Bonferroni-adjusted level of significance (P<1.79×10-3). The odds ratio was 1.20 (95% CI, 1.08-1.33; P=6.83×10-4) per 1-SD increase in macrophage migration inhibitory factor. Colocalization analyses supported our MR findings. Additionally, we found suggestive evidence between the genetic effects of stem cell growth factor-β and the risk of CAD (odds ratio, 0.95 [95% CI, 0.91-0.98]; P=0.007). Our findings suggested a risk-increasing effect of macrophage migration inhibitory factor level on the development of CAD. The roles of these inflammatory factors for CAD warrant further investigation.

Adverse COVID-19 outcomes in American Veterans with age-related macular degeneration: a case–control study

ObjectivesPrior studies suggest that patients with age-related macular degeneration (AMD) have poorer COVID-19 outcomes. This study aims to evaluate whether AMD is associated with adverse COVID-19 outcomes in a large...

Effect of different interfacial surface treatments on the shear bond strength of veneering ceramic and zirconia core

BackgroundSeveral interfacial surface treatments of zirconia surfaces have been proposed to improve adhesion to ceramic veneering. However, information regarding the durability and effect of such treatments on the bond strength following such treatments is lacking.Aim of the studyThis study aimed to evaluate the shear bond strength between veneering ceramic and zirconia core after different interfacial surface treatments.Materials and methodsFifty-two discs (8 mm in diameter and 3 mm in height) were fabricated from zirconia blanks using a microtome cutting machine. Zirconia discs were divided into four groups (n = 13). Group I was subjected to air-borne abrasion using (Al2O3), group II was coated by bioglass, group III was coated with ZirLiner, and group IV was subjected to wash firing (sprinkle technique). A cylinder (4 mm in diameter and 3 mm in height) of veneering ceramic was fired on top of the zirconia core. Shear bond strength (SBS) between zirconia core and veneering ceramic was evaluated by using a universal testing machine. The data was collected and statistically analysed using One-Way ANOVA followed by multiple pairwise comparisons using Bonferroni adjusted significance level. The failure modes were assessed using a stereomicroscope for each group.ResultsThe highest mean bond strength was recorded in group III (17.98 ± 2.51 MPa), followed by group II (15.10 ± 4.53 MPa), then group I 14.65 ± 2.97 MPa. The lowest mean bond strength was recorded in group IV (13.28 ± 3.55 MPa).ConclusionsSurface treatments had an effect on the zirconia-veneer shear bond strength. Liner coating revealed the highest shear bond strength values, significantly higher in comparison to wash firing (sprinkle technique) .

The Effect of Intravenous Lidocaine, Ketamine, and Lidocaine-Ketamine Combination in Colorectal Cancer Surgery: A Randomized Controlled Trial.

Colorectal resections are associated with a pronounced inflammatory response, severe postoperative pain, and postoperative ileus. The aim of this study was to evaluate the main effects of lidocaine and ketamine, and their interaction in colorectal cancer (CRC) patients after open surgery. The interaction could be additive if the effect of 2 drugs given in combination equals the sum of their individual effects, or multiplicative if their combined effect exceeds the sum of their individual effects. We hypothesized that the combination of lidocaine and ketamine might reduce the inflammatory response additively or synergistically. Eighty-two patients undergoing elective open colorectal resection were randomized to receive either lidocaine or placebo and either ketamine or placebo in a 2 × 2 factorial design. After induction of general anesthesia, all subjects received an intravenous bolus (lidocaine 1.5 mg/kg and/or ketamine 0.5 mg/kg and/or a matched saline volume) followed by a continuous infusion (lidocaine 2 mg·kg-1·h-1 and/or ketamine 0.2 mg·kg-1·h-1 and/or a matched saline volume) until the end of surgery. Primary outcomes were serum levels of white blood cell (WBC) count, interleukins (IL-6, IL-8), and C-reactive protein (CRP) measured at 2 time points: 12 and 36 hours after surgery. Secondary outcomes included intraoperative opioid consumption; visual analog scale (VAS) pain scores at 2, 4, 12, 24, 36, and 48 hours postoperatively; cumulative analgesic consumption within 48 hours after surgery; and time to first bowel movement. We assessed the main effects of each of lidocaine and ketamine and their interaction on the primary outcomes using linear regression analyses. A Bonferroni-adjusted significance level was set at .05/8 = .00625 for primary analyses. No statistically significant differences were observed with either lidocaine or ketamine intervention in any of the measured inflammatory markers. No multiplicative interaction between the 2 treatments was confirmed at 12 or 36 hours after surgery: WBC count, P = .870 and P = .393, respectively; IL-6, P = .892 and P = .343, respectively; IL-8, P = .999 and P = .996, respectively; and CRP, P = .014 and P = .445, respectively. With regard to inflammatory parameters, no evidence of additive interactions was found. Lidocaine and ketamine, either together or alone, significantly reduced intraoperative opioid consumption versus placebo, and, except for lidocaine alone, improved pain scores. Neither intervention significantly influenced gut motility. Our study results do not support the use of an intraoperative combination of lidocaine and ketamine in patients undergoing open surgery for CRC.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study

Several antiphospholipid antibody (aPL) profiles (“triple” and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-β2 glycoprotein-I antibody (aβ2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aβ2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aβ2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aβ2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Comparison of the color stability and surface roughness of 3-unit provisional fixed partial dentures fabricated by milling, conventional and different 3D printing fabrication techniques

ObjectivesTo compare the color stability and surface roughness of 3-unit provisional fixed partial dentures (FPDs) fabricated by milling, conventional, and different 3D printing fabrication techniques. MethodsA total sample of 160, 3-unit FPDs were subdivided into four groups; subtractive milled resin (SM), two 3D printed resins (Stereolithography; SLA and Digital Light Processing; DLP) and conventional self-cured polymethyl methacrylate resin (CM). Surface roughness (Ra) was assessed twice; at baseline (Ra1) and after artificial tooth brushing (Ra2). Color of the samples was measured after immersion in four different solutions (cola, coffee, black tea and distilled water) at three time intervals (1, 7 and 30 days). Comparisons of the Ra and the color change (∆E00) were done using one-way ANOVA followed by multiple pairwise comparisons using Bonferroni adjusted significance level. Comparisons of the Ra at two stages (Ra1 and Ra2) were done using paired t-test. Univariate linear regression was performed followed by multivariable regression to assess the association between ∆E00 and different factors (materials, solution, and time). Significance was set at P value <0.05. ResultsThe highest change in Ra following artificial tooth brushing was reported in the CM group, while the lowest change was reported in the SM group, with a significant difference between both groups (P<0.001). SM group had significantly lower ∆E00 than the CM group followed by 3D printed SLA and DLP groups (P<0.001). Storage in coffee for 30 days showed the highest ∆E00 values (P<0.001). ConclusionsSM resin showed the least surface roughness and color change followed by 3D printed SLA resin. The difference in printing technology affected the tested properties with improved readings of 3D printed SLA resin. Clinical significanceMilled provisional FPDs showed higher surface smoothness and color stability than those fabricated by SLA printing technology, but with no significant difference between both groups. Therefore, SLA printed resins can be an adequate substitute to milled resins in the fabrication of provisional FPDs to overcome the high expenses of milled provisional FPDs.

Skeletal and dentoalveolar characteristics of maxillary lateral incisor agenesis patients: a comparative cross-sectional study

BackgroundThe aim of the study was to evaluate the cephalometric and dentoalveolar characteristics of maxillary lateral incisor agenesis patients, and to compare the findings to a matched control group without tooth agenesis, excluding third molars, from the same population.MethodsThe pre-orthodontic records of 72 non-growing patients, who were treated at the Orthodontic Department, Faculty of Dentistry, Alexandria University, were used to address the aim of this retrospective study. Patients having unilateral or bilateral maxillary lateral incisor agenesis, with no history of previous orthodontic treatment, congenital craniofacial malformations, facial trauma, or surgeries were divided into two test groups based on the pattern of maxillary lateral incisors agenesis (group I: unilateral (UMLIA), group II: bilateral (BMLIA)). A control group (group III (CTRL)) having a complete set of permanent dentition (excluding third molars), and having no dental anomalies was age-matched with the test groups. Measurements were performed on the pre-orthodontic lateral cephalometric radiographs and the pre-orthodontic digital dental casts. The measured variables were compared between the groups using one-way ANOVA and Kruskal Wallis tests according to the normality of the variable. In case of significant results, both tests were followed by multiple pairwise comparisons using Bonferroni adjusted significance level. Significance level was set at P < 0.05.ResultsBMLIA group showed a smaller SNA angle and maxillary length, a more negative ANB angle and Wits appraisal, and a larger Maxillo-mandibular differential than UMLIA and/or CTRL group. The dental and soft tissue cephalometric measurements did not show any significant differences between the groups. Dentoalveolar cast measurements showed that BMLIA patients presented with significantly smaller maxillary inter-canine width than UMLIA and CTRL patients.ConclusionsCephalometric analysis has shown that subjects with BMLIA have a statistically significant reduced ANB and maxillary length. Tooth eruption may play a role in the development of the maxillary arch.

Association of Human Leukocyte Antigen Variants with Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Background: Multiple Myeloma (MM), a neoplasm of terminally differentiated plasma cells that produce a monoclonal immunoglobulin, represents 10% of hematologic malignancies. Virtually all MM arises from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant phase, at a rate of progression of about 1% annually. However, the risk of progression is not uniform as some individuals with MGUS could have progression rates as high as 58% in 20 years. Novel predictive markers are critically needed to accurately identify MGUS patients at high-risk of malignant transformation, so that early intervention can be implemented to prevent end-organ damage associated with frank myeloma. Genome-wide association studies (GWAS) have repeatedly identified loci at the major histocompatibility complex (MHC) that are associated with the risk of many cancers including MM. However, the impact of specific MHC loci on the MGUS-to-MM progression risk has not been elucidated. Methods: We used the Illumina Infinium Global Screening Array to scan the buffy coat samples of 259 MGUS and 654 MM patients enrolled from the Medical College of Wisconsin (MCW) Tissue Bank. All MGUS and MM patients have been chart reviewed and confirmed diagnosis. After a standard quality control (QC), 249 MGUS and 619 MM patients with 11,882 genotyped single nucleotide polymorphisms (SNPs) in the MHC region (20 to 40 mb at chromosome 6) were used for analysis. The SNP2HLA v1.0.3 software and HLA*IMP:03 were applied to impute classical human leukocyte antigen (HLA) alleles at a four-digit resolution based on SNP genotyping. SNP2HLA uses Beagle to impute all missing SNPs, classical HLA alleles, and amino acid polymorphisms to the HapMap reference panel. HLA*IMP:03 uses the Michigan Imputation Server to impute phased haplotypes to a multi-ethnic panel of 10,561 individuals with SNP genotype data and lab-based typing of alleles at 11 HLA genes. A post-imputation QC was conducted to remove variants with low imputation quality score (R2 < 0.3). Logistic regression analysis was performed using PLINK, a whole genome association analysis toolset, which adjusted for age, race, sex, and top principal components. Results: As evidenced by the quantile-quantile (QQ) plot (Figure 1), there was no evidence for hidden substructure or cryptic relatedness in the GWAS (λ=1.02). The final set of imputed variants from both tools used in association analysis were of high quality (R2 ≥0.9). Although we did not observe any HLA variants showing associations with the progression of MGUS to MM at Bonferroni adjusted significance level for SNP2HLA (P = 0.05/5865 = 8.53 × 10-6) and for HLA*IMP:03 (P = 0.05/215 = 2.33 × 10-4), we found 4 classical HLA alleles and 30 HLA Amino Acids were associated with MGUS progression at a P-value of < 0.05 via association analysis with SNP2HLA. Association analysis for HLA*IMP:03 imputation data identified 8 classical HLA alleles were associated with MGUS progression at P value < 0.05. Among them, two classical HLA alleles were identified in both tools, they are HLA_B*08:01 (odds ratio, OR=0.38, 95% confidence interval, CI =0.19-0.77 and OR=0.43, 95% CI=0.21-0.86 for SNP2HLA and HLA*IMP:03, respectively) and HLA_C*07:01 (OR=0.61, 95% CI=0.41-0.89 and OR=0.63, 95% CI=0.41-0.98 for SNP2HLA and HLA*IMP:03, respectively) (Table 1). Conclusions: These results implicate that HLA alleles may contribute to the progression of MGUS to MM. Further studies are needed to validate our findings with larger sample sizes and explore the biological mechanisms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

322-OR: ECG-Derived QRS-T Angle Is an Independent Predictor of Sudden Cardiac Death in Patients with Type 2 Diabetes: From the SURDIAGENE Prospective Study

Diabetes is associated with a high risk of sudden cardiac death (SCD) but the risk of non-SCD is even higher. We aimed to assess cardiac electrical markers for predicting SCD in patients with T2D. SURDIAGENE is a French prospective cohort of T2D patients. Baseline 12-lead ECG of 1285 (64±years; 43% female) patients were concordantly evaluated by 2 cardiologists to measure 15 ECG-derived markers. Causes of death were adjudicated by an independent committee. The primary outcome was SCD which was defined as a sudden, natural, and unexpected death, with preceding duration of symptoms &amp;lt;24 hours for witnessed cases and &amp;lt;1 hour witnessed cases. Bonferroni-adjusted cause-specific Cox proportional hazards and Fine and Gray competing-risk models were performed to identify independent predictors (adjustment for age, sex, HbA1c, NT-proBNP, eGFR, ACR, history of myocardial infarction, diuretic, and insulin) . At baseline, mean diabetes duration was 14±years and mean HbA1c 7.8±1.6%. During a median follow up of 7.4 years, 446 deaths occurred including 83 (18.6%) SCD. In univariate analysis, R wave voltage ≥mm in aVL lead, corrected QT interval and QRS-T angle ≥90° were associated with SCD risk at the Bonferroni-adjusted level of significance (P &amp;lt; 0.0033) . Using competing-risk multivariate analysis, QRS-T angle ≥90° only was significantly associated with a higher risk of SCD (sHR 1.63 [1.01-2.62]; P=0.045) but interestingly not with non-SCD (sHR 1.02 [0.78-1.33], P=0.87) . Discrimination of SCD prediction model was improved by QRS-T angle beyond multivariate Cox model parameters (C-statistic improved from 0.798 to 0.805, P&amp;lt;0.0001) . ECG-derived QRS-T angle is an independent predictor of SCD in patients with T2D and improves SCD-risk model prediction accuracy. Disclosure R.Garcia: Other Relationship; Abbott, Boston Scientific Corporation, Medtronic, Microport. The surdiagene study group: n/a. M.Tavernier: None. E.Gand: None. J.De keizer: None. B.Alos: None. C.Bouleti: Consultant; AstraZeneca, Novartis Pharmaceuticals Corporation, Research Support; Pfizer Inc. B.Degand: None. S.Hadjadj: Consultant; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novartis AG, Novo Nordisk, Sanofi, Servier Laboratories, Valbiotis, Other Relationship; Janssen Pharmaceuticals, Inc. P.Saulnier: Consultant; Grünenthal Group, Research Support; AstraZeneca, Novo Nordisk, Sanofi.

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy

Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. ClinicalTrials.gov Identifier: NCT01603407.

Comparison of the strain developed around implants with angled abutments with two reinforced polymeric CAD-CAM superstructure materials: An in vitro comparative study

Statement of problemThe strain developed around implants with angled abutments should be considered when selecting a superstructure material. Studies that evaluated the strain developed around implants with angled abutments when using fiber-reinforced polymer as the implant superstructure material are lacking. PurposeThe purpose of this in vitro study was to assess the strain developed around implants with angled abutments (15 and 25 degrees) of biocompatible high-performance polymer (BioHPP) and reinforced nanohybrid polymer with a multilayered glass fiber (TRINIA) superstructure under axial and oblique loading. The strain developed around implants was evaluated by using strain gauges. Material and methodsThirty-two polyurethane test blocks were divided into 2 main groups (n=16) according to the degrees of buccal tilting of the implant platform (15 and 25 degrees). Each group was divided into 2 subgroups (n=8), and each subgroup received different superstructure materials (BioHPP or TRINIA). Two buccal and palatal strain gauges were installed on their corresponding prepared sites to measure the microstrains in the medium surrounding the implant. A universal testing machine was used to apply the static load from 0 to 100 N in the axial and 45-degree oblique direction, with the loading tip of the device on the loading point at the central fossa of the crown. For each tested implant, loads were applied, microstrains were recorded with the strain gauges, and the strain developed around the implant was statistically evaluated with 1-way ANOVA, followed by multiple pairwise comparisons by using the Bonferroni adjusted significance level (α=.05). ResultsFor superstructure materials, the microstrain values recorded around implants restored with TRINIA were significantly lower than those restored with BioHPP in all groups (P<.001). The 25-degree implant angulation recorded significantly higher microstrain than 15 degrees buccally and palatally when axial and oblique loads were applied (P<.05). The microstrain was significantly higher in the oblique load than in the axial load in both the BioHPP and TRINIA groups in 15- and 25-degree implant angulations on the buccal and palatal sides (P<.001). ConclusionsThe strain developed around dental implants was significantly affected by the superstructure material. The microstrain was considerably higher when the implant abutment angulation increased. When a 45-degree loading direction was used, this tendency became more pronounced.

Prospective evaluation of multiplicative hybrid earthquake forecasting models in California

SUMMARYThe Regional Earthquake Likelihood Models (RELM) experiment, conducted within the Collaboratory for the Study of Earthquake Predictability (CSEP), showed that the smoothed seismicity (HKJ) model by Helmstetter et al. was the most informative time-independent earthquake model in California during the 2006–2010 evaluation period. The diversity of competing forecast hypotheses and geophysical data sets used in RELM was suitable for combining multiple models that could provide more informative earthquake forecasts than HKJ. Thus, Rhoades et al. created multiplicative hybrid models that involve the HKJ model as a baseline and one or more conjugate models. In retrospective evaluations, some hybrid models showed significant information gains over the HKJ forecast. Here, we prospectively assess the predictive skills of 16 hybrids and 6 original RELM forecasts at a 0.05 significance level, using a suite of traditional and new CSEP tests that rely on a Poisson and a binary likelihood function. In addition, we include consistency test results at a Bonferroni-adjusted significance level of 0.025 to address the problem of multiple tests. Furthermore, we compare the performance of each forecast to that of HKJ. The evaluation data set contains 40 target events recorded within the CSEP California testing region from 2011 January 1 to 2020 December 31, including the 2016 Hawthorne earthquake swarm in southwestern Nevada and the 2019 Ridgecrest sequence. Consistency test results show that most forecasting models overestimate the number of earthquakes and struggle to explain the spatial distribution of epicenters, especially in the case of seismicity clusters. The binary likelihood function significantly reduces the sensitivity of spatial log-likelihood scores to clustering, however; most models still fail to adequately describe spatial earthquake patterns. Contrary to retrospective analyses, our prospective test results show that none of the models are significantly more informative than the HKJ benchmark forecast, which we interpret to be due to temporal instabilities in the fit that forms hybrids. These results suggest that smoothing high-resolution, small earthquake data remains a robust method for forecasting moderate-to-large earthquakes over a period of 5–15 yr in California.

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.

Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P=3.27×10-30) and MMP-3 (β=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Abstract 9897: Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults

Introduction: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Hypothesis: Whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry will increase power to identify novel genetic determinants. Methods: Proteomic profiling of 1,301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan®). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥ 5. Results were validated using an alternative, antibody-based, proteomic platform (Olink®) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study. Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8 х 10 -11 . These associations include 134 novel locus-protein relationships and an additional 205 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β = 0.61±0.05, p-value = 3.27 х 10 -30 ) and MMP-3 (β = -0.60±0.05, p = 1.67 х 10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with nine proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1 associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β = 0.34±0.04, p = 1.34 х 10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community dwelling individuals without heart failure. Discussion: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation and myocardial function.

Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test.

Cutaneous squamous cell carcinoma (cSCC) accounts for about 20% of all skin cancers, the most common type of malignancy in the United States. Genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with the risk of cSCC. Most of these studies were single-locus-based, testing genetic variants one-at-a-time. In this article, we performed gene-based association tests to evaluate the joint effect of multiple variants, especially rare variants, on the risk of cSCC by using a fast sequence kernel association test (fastSKAT). The study included 1,710 cSCC cases and 24,304 cancer-free controls from the Nurses’ Health Study, the Nurses’ Health Study II and the Health Professionals Follow-up Study. We used UCSC Genome Browser to define gene units as candidate loci, and further evaluated the association between all variants within each gene unit and disease outcome. Four genes HP1BP3, DAG1, SEPT7P2, and SLFN12 were identified using Bonferroni adjusted significance level. Our study is complementary to the existing GWASs, and our findings may provide additional insights into the etiology of cSCC. Further studies are needed to validate these findings.

Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers.

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study.

ObjectiveExtensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM.Design, Setting, and ParticipantsTwo-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes—insomnia, sleep duration, short sleep duration, long sleep duration, and morningness—were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM).Main MethodsIndividual Cochran’s Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings.ResultsTwo-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09–1.19, p = 1.29E–08) at the Bonferroni-adjusted level of significance (p < 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses.ConclusionFindings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM.