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To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.

Objective: To evaluate changes in toothbrushing behaviour and plaque removal performance with usage of a next generation oscillating‐rotating electric toothbrush (NG‐OR). Methods: This exploratory clinical study had a two‐treatment, three‐period, single‐group, sequential design. Generally healthy adults with a screening whole mouth mean Turesky modified Quigley‐Hein Plaque Index (TQHPI) score of at least 1.75 on a 0–5 scale and who were primarily OR brush users were enrolled. Participants used each OR toothbrush in A‐B‐B order, where a currently marketed OR brush with a traditional mechanical drive system (T‐OR) was used in period A, and the NG‐OR brush with a linear magnetic drive was used in period B. At Visit 1, qualifying participants brushed on‐site with T‐OR. After a 48 h washout, participants returned for Visit 2 and brushed on‐site with NG‐OR. Participants then used NG‐OR for 1 week, twice daily, at home and returned for Visit 3 to brush on‐site with NG‐OR again. For all on‐site brushings, participants were instructed to brush for 2 min without interactive features. Each toothbrush was tagged with a transmitter chip connected to a Motion Tracking System to record movements of the toothbrush and participant using infrared light transmission to determine Isochronicity (brushing time uniformly distributed across the dentition). Plaque was measured using TQHPI. Primary variables were Isochronicity and TQHPl whole mouth mean plaque reduction (pre‐brushing minus post‐brushing). Results: Overall, 41 participants enrolled and received treatment; 40 completed the trial. NG‐OR showed significantly greater Isochronicity after a single brushing (p = 0.043) and after a 1‐week at‐home use (p = 0.001) versus T‐OR. NG‐OR showed 41% greater whole mouth plaque removal than T‐OR (p < 0.001) after a single brushing. Plaque reduction by region/surface was consistent with whole mouth results. Conclusion: The NG‐OR brush showed greater brushing uniformity and plaque removal versus the T‐OR brush. [ABSTRACT FROM AUTHOR]

Background Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, 'brand') product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. Methods and findings From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (C.sub.max) (range 17.96-24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and C.sub.max, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and C.sub.max in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study. Conclusions Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other. Trial registration ClinicalTrials.gov NCT01889758., Author(s): Rita R. Alloway 1,*, Alexander A. Vinks 2,3, Tsuyoshi Fukuda 2,3, Tomoyuki Mizuno 2,3, Eileen C. King 3,4, Yuanshu Zou 3,4, Wenlei Jiang 5, E. Steve Woodle 6, Simon [...]

Objective: To assess the anti-gingivitis and anti-plaque efficacy of a novel bioavailable stannous fluoride (SnF2) dentifrice to a negative control.Methods: This was a 12-week randomized, controlled, double-blind, two-treatment, parallel group clinical study. One hundred generally healthy adults with evidence of plaque and gingivitis were enrolled into the study. Subjects were randomly assigned to one of two dentifrice treatments: (1) novel SnF2 dentifrice containing the amino acid glycine as a stabilizing chelant (Procter and Gamble) or (2) a negative control sodium monofluorophosphate dentifrice. Gingivitis was assessed using the Löe-Silness Gingivitis Index (LSGI) at baseline, Week 1, and Week 12 while plaque was evaluated according to the Turesky Modification of the Quigley-Hein Plaque Index at baseline and Week 12.Results: One hundred subjects completed the trial. Subjects using the novel SnF2 dentifrice demonstrated statistically significantly fewer bleeding sites and a lower LSGI score versus those using the negative control as early as Week 1 (P less than .001). The benefit increased throughout the study, with the SnF2 dentifrice showing 33.4% fewer bleeding sites and a 16.5% lower LSGI score versus the negative control at Week 12 (P less than .001). Subjects with localized or generalized gingivitis (≥10% bleeding sites) had 6 times better odds of transitioning to generally healthy (less than 10% bleeding sites) after using the SnF2 dentifrice for 12 weeks versus the negative control. Plaque scores for the SnF2 dentifrice were also statistically significantly lower (P less than .001) than those for the negative control at Week 12.Conclusion: The novel SnF2 dentifrice with the amino acid glycine produced statistically significant improvements in gingival health that were seen as early as 1 week and numerically increased throughout the study. [ABSTRACT FROM AUTHOR]

Studies of religious/spiritual behavior frequently rely on self-reported questionnaire data, which is susceptible to bias. The Daily Phone Diary (DPD) was developed to minimize bias in reporting activities and behavior across a 24-hour period. A cross-sectional study of 126 parents of children with cystic fibrosis was used to establish the validity of the DPD to study religious/spiritual behaviors. Longitudinal models were used to determine the odds of improved mood during religious/spiritual activities. Convergent validity was found. Participants had increased odds of improved mood during religious/spiritual activities compared to nonreligious/spiritual activities. Associations with gender and religious affiliations were found. The DPD is a valid tool for studying religious/spiritual activities and opens novel avenues for chaplaincy research and the development of chaplaincy interventions incorporating these findings. [ABSTRACT FROM AUTHOR]

Understanding how long-term marital stress affects major depressive disorder (MDD) in older women has clinical implications for the treatment of women at risk. In this paper, we consider the problem of predicting MDD in older women (mean age 60) from a marital stress scale administered four times during the preceding 20-year period, with a greater dropout by women experiencing marital stress or MDD. To analyze these data, we propose a Bayesian joint model consisting of: (1) a linear mixed effects model for the longitudinal measurements, (2) a generalized linear model for the binary primary endpoint, and (3) a shared parameter model for the missing data mechanism. Our analysis indicates that MDD in older women is significantly associated with higher levels of prior marital stress and increasing marital stress over time, although there is a generally decreasing trend in marital stress. This is the first study to propose a joint model for incompletely observed longitudinal measurements, a binary primary endpoint, and non-ignorable missing data; a comparison shows that the joint model yields better predictive accuracy than a two-stage model. These findings suggest that women who experience marital stress in mid-life need treatment to help prevent late-life MDD, which has serious consequences for older persons. [ABSTRACT FROM AUTHOR]

Purpose To evaluate changes in toothbrushing behavior and plaque removal performance with usage of a next generation oscillating-rotating electric toothbrush (NG-OR). Methods This exploratory clinical study had a two-treatment, three-period, single-group, sequential design. Generally healthy adults with a screening whole mouth mean Turesky modified Quigley-Hein Plaque Index (TQHPI) score of at least 1.75 on a 0-5 scale and who were primarily OR brush users were enrolled. Participants used each OR toothbrush in A-B-B order, where a currently marketed OR brush with a traditional mechanical drive system (T-OR) was used in period A and the NG-OR brush with a linear magnetic drive was used in period B. At Visit 1, qualifying participants brushed on-site with T-OR. After a 48h washout, participants returned for Visit 2 and brushed on-site with NG-OR. Participants then used NG-OR for 1 week, twice daily, at home and returned for Visit 3 to brush on-site with NG-OR again. For all on-site brushings, participants were instructed to brush for 2min without interactive features. Each toothbrush was tagged with a transmitter chip connected to a Motion Tracking System to record movements of the toothbrush and participant using infrared light transmission to determine Isochronicity (brushing time uniformly distributed across the dentition). Plaque was measured using TQHPI. Primary variables were Isochronicity and TQHPl whole mouth mean plaque reduction (pre-brushing minus post brushing). Results Overall, 41 participants enrolled and received treatment; 40 completed the trial. NG-OR showed significantly greater Isochronicity after a single brushing ( p =0.043) and after a 1-week at-home use ( p =0.001) versus T-OR. NG-OR showed 41% greater whole mouth plaque removal than T-OR ( p <0.001) after a single brushing. Plaque reduction by region/surface was consistent with whole mouth results. Conclusion The NG-OR brush showed greater brushing uniformity and plaque removal versus the T-OR brush., (Copyright © 2023 The American Dental Hygienists’ Association.)

Purpose: To evaluate the antiplaque effects for 0.454% bioavailable gluconate chelated stannous fluoride (SnF₂) dentifrices versus controls by clinical model, plaque index, tooth surface and tooth type in a pooled analysis., Methods: Randomized controlled trials (RCTs) were conducted to evaluate plaque effects of SnF₂ dentifrices from the same formulation family over the past 30 years. Forty-four 4-day and longer-term (≥ 2 weeks) RCTs conducted in six countries with 3,336 subjects using Turesky Modified Quigley-Hein Plaque Index, Rustogi Modification of the Navy Plaque Index, Digital Plaque Imaging Analysis, and Silness and Löe Plaque Index were included., Results: In 13 and 11 longer-term studies assessing SnF₂ dentifrice versus a negative or positive control, respectively, standardized differences in average plaque score of -1.15 (95% CI: -1.61, -0.69) and -0.74 (95% CI: -1.20, -0.28) were observed (P ≤ 0.011), favoring SnF₂. Reductions represented a 19% and 16% benefit versus the negative and positive control, respectively. In 18 and five 4-day studies assessing SnF₂ dentifrice versus a negative (NaF/SMFP) or positive (triclosan/chlorhexidine) control, respectively, differences in average 4-day plaque score of -0.27 (95% CI: -0.31, -0.23) and -0.15 (95% CI: -0.25, -0.06) were observed (P≤ 0.001) favoring SnF₂. Reductions represented a 14% and 11% benefit versus the negative and positive control, respectively. Significant antiplaque benefits for SnF₂ dentifrice were seen regardless of clinical model, plaque index, tooth surface or type, including brushed and unbrushed surfaces (P≤ 0.049)., Clinical Significance: Bioavailable gluconate chelated SnF₂ dentifrices showed consistent plaque inhibition versus negative and positive controls across all conditions evaluated. Importantly, the effect on unbrushed surfaces illustrated the significant plaque inhibition benefit of SnF₂ beyond mechanical plaque removal., Competing Interests: All authors are employees of The Procter & Gamble Company. This work was funded by The Procter & Gamble Company., (Copyright©American Journal of Dentistry.)

Purpose: To compare the effects of oscillating-rotating (O-R), sonic (side-to-side), and manual toothbrushes on plaque and gingival health after multiple uses in studies up to 3 months., Methods: A meta-analysis was conducted on randomized clinical trials (RCTs) up to 3 months in duration to evaluate O-R electric toothbrush effectiveness regarding gingivitis reduction and plaque removal versus sonic and/or manual toothbrushes. To ensure access to subject-level data, this meta-analysis was limited to RCTs involving O-R toothbrushes from a single manufacturer conducted from 2007 to 2017 for which subject-level data were available and that satisfied criteria of duration, parallel design, examiner-graded, etc. For gingivitis studies, a one-step individual subject meta-analysis was used to assess direct and indirect treatment differences and to identify any subject-level covariates modifying treatment effects. In the two-step meta-analysis, individual participant data were first analyzed in each study independently using the last timepoint (up to 3 months), producing aggregate data for each study. Then forest plots were produced using these aggregate data with random-effects models. For plaque studies, the efficacy variables were standardized so direct comparisons could be generated using the 2-step meta-analysis. Network meta-analysis was performed to assess the indirect plaque comparisons., Results: 16 parallel group RCTs with 2,145 subjects were identified assessing gingivitis via number of bleeding sites. In five and 11 gingivitis studies assessing O-R brushes versus manual and sonic brushes, respectively, a change in the average number of bleeding sites of -8.9 ( 95% CI: -15.9, -1.9) and -3.1 (95% CI: -3.8, -2.4) was observed (P ≤ 0.008). These reductions equate to a 50% and 28% bleeding benefit for O-R technology versus the respective controls. The sonic brush bleeding change versus manual was -5.9 (P = 0.062), a 34% bleeding benefit. Utilizing individual bleeding scores, subjects with localized or generalized gingivitis (≥ 10% bleeding sites) had 7.4 times better odds of transitioning to generally healthy (< 10% bleeding sites) after using an O-R brush versus manual. 20 parallel design RCTs with 2,551 subjects assessed plaque (TMQHI, RMNPI). In eight and 12 plaque RCTs assessing an O-R brush versus manual and sonic brushes, respectively, standardized changes in average plaque scores of -1.51 (95% CI: -2.17, -0.85) and -0.55 (95% CI: -0.82, -0.28) were observed (P< 0.001). These plaque reductions by O-R equate to a relative 20% and 4% greater benefit, respectively. The change for sonic versus manual was -0.93 ( 95% CI:-1.48, -0.38); (P < 0.001) which equates to a 12% plaque benefit., Clinical Significance: This subject-level meta-analysis of studies up to 3 months provides sound evidence supporting recommendations for patients with various degrees of gingival bleeding to use oscillating-rotating electric toothbrushes over manual and sonic toothbrushes to improve plaque control and gingival health., Competing Interests: The authors are employees of The Procter & Gamble Company., (Copyright©American Journal of Dentistry.)

Purpose: To further validate the ability of ultrashort echo-time (UTE) magnetic resonance imaging (MRI) in quantifying lung density in patients diagnosed with chronic obstructive pulmonary disease (COPD) and to develop an MRI-based emphysema index (EI)., Materials and Methods: Ten subjects clinically diagnosed with COPD (5M/5F, age 62.6 ± 8.5 years) and ten healthy subjects (2M/8F, age 48.9 ± 19.2 years) were imaged via UTE MRI at 3T (4 mm slices, 1.39 × 1.39 mm 2 pixels). Chest computed tomography (CT) images (generally 5 mm slices, ≈0.55 × 0.55 mm 2 pixels), acquired retrospectively, were compared to UTE MRI. CT lung densities, MR lung-signal density, and EI were quantified from both CT and UTE MR images via a quantitative automated analysis and compared to the percent predicted forced expiratory volume in 1 second (FEV 1 % predicted)., Results: EI quantified in controls via CT and UTE MRI was 0.23 ± 0.78% and 2.40 ± 1.50%, respectively; in COPD subjects it was 13.3 ± 14.9% (P = 0.021) and 12.0 ± 9.8% (P = 0.013), respectively. Bland-Altman determined the mean differences and 95% limits of agreement for COPD subjects and healthy controls were 0.06 (12.50 to -12.38). Strong correlation (R 2  = 0.79, P < 0.0001) existed between EIs quantified from both CT and UTE MRI. There was a slightly higher correlation between FEV 1 % predicted and the UTE MRI EI (R 2  = 0.65, P < 0.0001) compared to CT EI (R 2  = 0.49, P < 0.0001)., Conclusion: Our results demonstrate a significant positive correlation between lung density and EI assessed with CT and MRI. Furthermore, UTE MRI exhibits its potential as a diagnostic alternative to CT for assessing the extent and the severity of emphysema, particularly for longitudinal studies. J. Magn. Reson. Imaging 2016;44:1656-1663., (© 2016 International Society for Magnetic Resonance in Medicine.)