Recurrence in Oral Premalignancy: Clinicopathologic and Immunohistochemical Analysis.

Oral leukoplakia (OL) has a propensity for recurrence and malignant transformation (MT). Herein, we evaluate sociodemographic, clinical, microscopic and immunohistochemical parameters as predictive factors for OL recurrence, also comparing primary lesions (PLs) with recurrences. Thirty-three patients with OL, completely removed either by excisional biopsy or by laser ablation following incisional biopsy, were studied. Selected molecules associated with the STAT3 oncogenic pathway, including pSTAT3, Bcl-xL, survivin, cyclin D1 and Ki-67, were further analyzed. A total of 135 OL lesions, including 97 PLs and 38 recurrences, were included. Out of 97 PLs, 31 recurred at least once and none of them underwent MT, during a mean follow-up time of 48.3 months. There was no statistically significant difference among the various parameters in recurrent vs. non-recurrent PLs, although recurrence was most frequent in non-homogeneous lesions (p = 0.087) and dysplastic lesions recurred at a higher percentage compared to hyperplastic lesions (34.5% vs. 15.4%). Lower levels of Bcl-xL and survivin were identified as significant risk factors for OL recurrence. Recurrences, although smaller and more frequently homogeneous and non-dysplastic compared to their corresponding PLs, exhibited increased immunohistochemical expression of oncogenic molecules, especially pSTAT3 and Bcl-xL. Our results suggest that parameters associated with recurrence may differ from those that affect the risk of progression to malignancy and support OL management protocols favoring excision and close monitoring of all lesions.

Dissection of Bitcoin's multiscale bubble history from January 2012 to February 2018.

We present a detailed bubble analysis of the Bitcoin to US Dollar price dynamics from January 2012 to February 2018. We introduce a robust automatic peak detection method that classifies price time series into periods of uninterrupted market growth (drawups) and regimes of uninterrupted market decrease (drawdowns). In combination with the Lagrange Regularization Method for detecting the beginning of a new market regime, we identify three major peaks and 10 additional smaller peaks, that have punctuated the dynamics of Bitcoin price during the analysed time period. We explain this classification of long and short bubbles by a number of quantitative metrics and graphs to understand the main socio-economic drivers behind the ascent of Bitcoin over this period. Then, a detailed analysis of the growing risks associated with the three long bubbles using the Log-Periodic Power-Law Singularity (LPPLS) model is based on the LPPLS Confidence Indicators, defined as the fraction of qualified fits of the LPPLS model over multiple time windows. Furthermore, for various fictitious 'present' times t 2 before the crashes, we employ a clustering method to group the predicted critical times t c of the LPPLS fits over different time scales, where t c is the most probable time for the ending of the bubble. Each cluster is proposed as a plausible scenario for the subsequent Bitcoin price evolution. We present these predictions for the three long bubbles and the four short bubbles that our time scale of analysis was able to resolve. Overall, our predictive scheme provides useful information to warn of an imminent crash risk.

Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. METHODS: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. RESULTS: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. CONCLUSIONS: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.

Influence of nonsteroidal anti-inflammatory drugs on osseointegration.

This paper reviews contemporary literature concerning the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on osseointegration. In vitro studies concerning the effect of NSAIDs on growth factors and bone-generating cells are the primary source of data pertaining to this issue because relatively few in vivo studies have been conducted. It is concluded that prescribing NSAIDs during the early postoperative period is likely not without negative effect, although any negative influence appears to be temporary and does not affect the final outcome of osseointegration.