PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability.

53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.

Measuring Gait Parameters from Structural Vibrations.

Measuring gait parameters (e.g. speed, cadence, step duration) accurately is invaluable for evaluation during treatment of older adults who struggle with disability onset, disease progression, balance, and injurious falls. Traditionally stopwatches or timing gates are used to measure gait speed in clinical settings, and these are limited to measuring gait speed. Other wearable and non-wearable technologies offer the ability to measure additional gait parameters though patients are known to walk differently with the devices and even tend to slow down before engaging with a non-wearable such as a floor mat. Floor vibrations are a promising option to measuring gait parameters while not being intrusive and not requiring line-of-sight to the patient for measurements. This paper presents methodology for extracting gait parameters using vibrations with comparisons to APDM Wearable Technologies Mobility Lab sensors and stopwatch measurements. Performance is examined across 97 participants for self-selected speed forward, full speed forward, and backwards walks at three different testing sites for a total of 1039 walks. Gait speed vibrations measurements demonstrated excellent reliability with APDM Mobility Lab (ICC: 0.98; 99% CI: 0.01±0.01 m/s) and stopwatch (ICC: 0.97; 99% CI: -0.01±0.01 m/s) measurements. Similar excellent results are reported for cadence, gait cycle duration, step duration, and stride length parameters.

Efficacy of disintegrating aspirin in two different models for acute mild-to-moderate pain: sore throat pain and dental pain.

A recently developed fast-release aspirin tablet formulation has been evaluated in two different pain models. The dental impaction pain model and the sore throat pain model are widely used for assessing analgesia, including acute mild-to-moderate pain. Both studies were double-blind, randomized, parallel group and compared a single dose of 1000 mg aspirin with 1000 mg paracetamol and with placebo and investigated the onset and overall time course of pain relief. Speed of onset was measured by the double-stopwatch method for time to meaningful pain relief and time to first perceptible pain relief. Pain intensity and pain relief were rated subjectively over a 6-h (dental pain) and 2-h (sore throat pain) time period. In both models fast-release aspirin and commercial paracetamol were statistically significantly different from placebo for onset of action, summed pain intensity differences and total pain relief. Meaningful pain relief was achieved within a median of 42.3 and 42.9 min for aspirin and paracetamol, respectively, in the dental pain model. The corresponding numbers in sore throat pain were 48.0 and 40.4 min. All treatments in both studies were safe and well tolerated. No serious adverse events were reported and no subject was discontinued due to an adverse event. Overall the two studies clearly demonstrated efficacy over placebo in the two pain models and a comparable efficacy and safety profile between aspirin and an equivalent dose of paracetamol under the conditions of acute dental pain and acute sore throat pain. Trial registration These trials were registered with ClinicalTrials.gov, registration number: NCT01420094, registration date: July 27, 2011 and registration number: NCT01453400, registration date: October 13, 2011.

Validity and Reliability of a Smartphone Application for Home Measurement of Four-Meter Gait Speed in Older Adults.

The four-meter gait speed (4MGS) is a recommended physical performance test in older adults but is challenging to implement clinically. We developed a smartphone application (App) with a four-meter ribbon for remote 4MGS testing at home. This study aimed to assess the validity and reliability of this smartphone App-based assessment of the home 4MGS. We assessed the validity of the smartphone App by comparing it against a gold standard video assessment of the 4MGS conducted by study staff visiting community-dwelling older adults and against the stopwatch-based measurement. Moreover, we assessed the test-retest reliability in two supervised sessions and three additional sessions performed by the participants independently, without staff supervision. The 4MGS measured by the smartphone App was highly correlated with video-based 4MGS (r = 0.94), with minimal differences (mean = 0.07 m/s, ± 1.96 SD = 0.12) across a range of gait speeds. The test-retest reliability for the smartphone App 4MGS was high (ICC values: 0.75 to 0.93). The home 4MGS in older adults can be measured accurately and reliably using a smartphone in the pants pocket and a four-meter strip of ribbon. Leveraging existing technology carried by a significant portion of the older adult population could overcome barriers in busy clinical settings for this well-established objective mobility test.

Highly Visible Wall-Timer to Reduce Endovascular Treatment Time for Stroke.

BACKGROUND: Endovascular therapy for acute ischemic stroke has revolutionized clinical care for patients with stroke and large vessel occlusion, but treatment remains time sensitive. At our stroke center, up to half of the door-to-groin time is accounted for after the patient arrives in the angio-suite. Here, we apply the concept of a highly visible timer in the angio-suite to quantify the impact on endovascular treatment time. METHODS: This was a single-center prospective pseudorandomized study conducted over a 32-week period. Pseudorandomization was achieved by turning the timer on and off in 2-week intervals. The primary outcome was angio-suite-to-groin time, and secondary outcomes were angio-suite-to-intubation time, groin-to-recanalization time, and 90-day modified Rankin scale. A stratified analysis was performed based on type of anesthesia (ie, endotracheal intubation versus not). RESULTS: During the 32-week study period, 97 mechanical thrombectomies were performed. The timer was on and off for 38 and 59 cases, respectively. The timer resulted in faster angio-suite-to-groin time (28 versus 33 minutes; P=0.02). The 5-minute reduction in angio-suite-to-groin was maintained after adjusting for intubation status in a multivariate regression (P=0.02). There was no difference in the 90-day modified Rankin scale between groups. The timer impact was consistent across the 32-week study period. CONCLUSIONS: A highly visible timer in the angio-suite achieved a meaningful, albeit modest, reduction in endovascular treatment time for patients with stroke. Given the lack of risk and low cost, it is reasonable for stroke centers to consider a highly visible timer in the angio-suite to improve treatment times.

Evaluation of the Limb Symmetry Index: The Side Hop Test.

The main objective of present study was to evaluate inter-rater reliability and concurrent validity of Side Hop Test stopwatch vs. force plates timing, and to determine the number of sessions and trials required to minimize the effects of learning on Side Hop Test total time and limb symmetry index. Fifteen healthy male physical education students (mean ± SD: age, 23 ± 3 years; height, 181 ± 9 cm; and weight 72 ± 6 kg) participated. Side Hop Test total time (stopwatch and force plates) of left and right leg, and limb symmetry index (force plates) were obtained over seven sessions conducted 5-7 days apart. Time recordings of two raters were similar (t = -0.56, p > 0.05) with high reliability (all ICC >0.99 and CV% <0.1) and no systematic bias when compared to force plate data (p > 0.05; for rater 1 and 2, respectively). Total time improved across the Sessions (F = 25.87, p < 0.01, ω 2 = 0.18) and Trials (F = 68.15, p < 0.01, ω 2 = 0.10), with no significant interaction between factors. No between-leg differences were detected (F = 0.52, p > 0.05, ω 2 = 0.001). Limb symmetry index ranged from 0.999 to 1.055 across all sessions and trials (all p > 0.05 and ω 2 < 0.00). Due to low coefficient of correlation, high interclass correlation coefficient, and the lack in heteroscedasticity, stopwatch measurements are valid to measure total time in the Side Hop Test. Moreover, stopwatch measurements could be reliably used to measure total time in the Side Hop Test, while the test could be administrated with only one experienced rater. Unlike total times, findings on limb symmetry index suggest it could be reliably assessed after seven familiarization sessions.

Validation of Accelerometry Data to Identify Movement Patterns During Agility Testing.

Purpose: The purpose of this study was to develop an algorithm for the detection and timing of foot contact/off timing for each lateral repetition and assess the validity/reliability of the calculated timings. Methods: Participants performed a modified Edgren Side Step Test in which they moved laterally along a 4-m path as quickly as possible while wearing an accelerometer on each ankle. Time of completion of each attempt was recorded using a stopwatch and digital video was obtained. Accelerometer-based (ACC) events were determined for the start of the test (START), foot contact at the end-line (FC) and the lifting of the foot when transitioning to the other direction (FO). Based on these ACC events the Overall, Split (ST) and Lag (LT) times were determined and compared to either the stopwatch or video-based timings (p < 0.05). The ACC event criterion was then applied by independent reviewers to assess inter/intra-rater reliability of identifying the events. Results: There was no significant difference in ACC (12.37 ± 2.19 s) based Overall Time compared to the Stopwatch (12.42 ± 2.25 s, p = 0.34). Bland-Altman plots for ST and LT revealed very good agreement between the ACC time to the Video (ST: Bias = 0.11 s, LOA -0.57 to 0.79; LT: Bias = -0.11 s, LOA -0.43 to 0.22). Intra and inter-rater reliability was moderate to excellent for all reviewer identified events. Conclusions: This study demonstrates methodology to identify ACC based timings during an agility test. The inclusion of an accelerometer supplements standard timing options with the added benefit of assessing sided split and lag times.

Dual-task gait speed assessments with an electronic walkway and a stopwatch in older adults. A reliability study.

BACKGROUND/OBJECTIVES: Slow gait speed prospectively predicts elevated risk of adverse events such as falls, morbidity, and mortality. Additionally, gait speed under a cognitively demanding challenge (dual-task gait) predicts further cognitive decline and dementia incidence. This evidence has been mostly collected using electronic walkways; however, not all clinical set ups have an electronic walkway and comparability with simple manual dual-gait speed testing, like a stopwatch, has not yet been examined. Our main objective was to assess concurrent-validity and reliability of gait speed assessments during dual-tasking using a stopwatch and electronic walkway in older adults with mild and subjective cognitive impairment (MCI and SCI). DESIGN: Cross-sectional, reliability study. SETTING: Clinic based laboratory at an academic hospital in London, ON, Canada. PARTICIPANTS: 237 walk tests from 34 community-dwelling participants (mean age 71.84 SD 5.38; 21 female - 62%, 13 male - 38%) with SCI and MCI. were included from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. INTERVENTION: Each participant performed seven walk tests: three single gait walks at their normal pace, three dual-task walks (walking and counting backwards by one, by sevens, and naming animals), and one fast walk. MEASUREMENTS: Gait speed (cm/s) for each walk was measured simultaneously with an electronic walkway (Zeno Mat®) and a handheld stopwatch (Ultrak chronometer®). Dual-task cost (DTC) was calculated for the three individual dual-task walks as [((single gait speed - dual-task gait speed) / single gait speed) ∗ 100]. Level of agreement between the two measurement methods was analyzed using Pearson correlations, paired t-tests, and Bland-Altman plots. RESULTS: Gait speed was consistently lower when measured with the stopwatch than with the electronic walkway (mean speed difference: 10.6 cm/s ± 5.1, p < 0.001). Calculating DTC, however, yielded very similar results with both methods (mean DTC difference: 0.19 ± 1.18, p = 0.872). The higher the DTC, the closer the measurement between methods. CONCLUSION: Assessing and calculating DTC with a stopwatch is simple, accessible and reliable. Its validity and reliability were high in this clinical sample of community older adults with SCI and MCI.

Comparison of the use of a manual stopwatch and an automatic instrument for measuring 4-m gait speed at the usual walking pace with different starting protocols in older adults.

PURPOSE: This study compared manual stopwatch-based and automatic instrument-based measurements for gait speed (GS) obtained from the individual's usual walking pace using a 4-m walking test with different starting protocols in healthy older adults. METHODS: One hundred fifty-three healthy older adults aged ≥ 65 years (57 men, 96 women) participated. GS was measured using both a stopwatch and automatic timer with or without 2-m acceleration and deceleration phases. In the GS measurement using the stopwatch, the first tester stood in the middle of the timing zone (MS1) while the second walked beside the participants from the beginning line to the ending line (MS2). RESULTS: In the manual method, MS1 and MS2 showed similar GS for both standing and moving starts. There was no significant difference in GS measured between with the manual stopwatch and with the automatic timer in standing start. However, in the moving start protocol, GS measured with the manual stopwatch was significantly faster, by 0.05 m/s in MS1 (p < 0.001) and 0.04 m/s in MS2 (p < 0.001) compared to the timed GS with the automatic timer. GS measured manually using a moving start was significantly faster than that measured manually using a standing start (MS1, 0.06 m/s, 5.0%, p < 0.001; MS2, 0.08 m/s, 6.8%, p < 0.001); however, there was no difference between the start protocols when automatic measurements were performed (p = 0.135). CONCLUSIONS: The starting protocol (starting and moving start) affected the usual 4-m GS when measured using a manual stopwatch. Therefore, we suggest that careful evaluation to measure GS for functional assessment of older adults using the moving start with a manual stopwatch.

Onset of analgesia by a topically administered flurbiprofen lozenge: a randomised controlled trial using the double stopwatch method.

BACKGROUND: The double stopwatch (DSW) method for determining the onset of analgesic activity has been implemented extensively by investigators studying orally administered drugs. OBJECTIVE: The aim of this randomised, placebo-controlled trial was to use the DSW method to determine the time to onset of analgesia of a single dose of a topically administered non-steroidal anti-inflammatory drug, flurbiprofen 8.75 mg lozenge. METHODS: Adults with acute sore throat (n = 122) were examined to confirm the presence of tonsillopharyngitis (Tonsillo-Pharyngitis Assessment) and sore throat pain of at least moderate intensity (≥6 on a 0-10 Sore Throat Scale). Lozenges containing flurbiprofen 8.75 mg or inert ingredients (identically flavoured) were administered under double-blind conditions in the clinic while patients assessed pain and pain relief over 3 hours. Onset of analgesia was determined using the DSW method and reported as the Kaplan-Meier median time to meaningful relief. The median time to first perceived relief was also documented. RESULTS: About 78% of flurbiprofen-treated patients reported meaningful pain relief compared with 48% of placebo-treated patients (p < 0.01); median time to meaningful relief for flurbiprofen-treated patients was 43 minutes (placebo-treated patients were right-censored due to non-responsivity; p = 0.01). Median time to first perceived pain relief was 11 minutes for flurbiprofen-treated patients and 19 minutes for placebo-treated patients (p = 0.03). Flurbiprofen lozenge was well tolerated, with no serious adverse events occurring and no patient discontinuing due to an adverse event. CONCLUSION: These results indicate that the DSW method can be successfully applied to the evaluation of the onset of action of a locally administered analgesic in patients with acute sore throat, demonstrating that the onset of action (time to meaningful pain relief) of flurbiprofen lozenge was <45 minutes.

An evaluation of 10 percent and 20 percent benzocaine gels in patients with acute toothaches: efficacy, tolerability and compliance with label dose administration directions.

BACKGROUND: The authors evaluated the efficacy and tolerability of 10 percent and 20 percent benzocaine gels compared with those of a vehicle (placebo) gel for the temporary relief of toothache pain. They also assessed the compliance with the label dose administration directions on the part of participants with toothache pain. METHODS: Under double-masked conditions, 576 participants self-applied study gel to an open tooth cavity and surrounding oral tissues. Participants evaluated their pain intensity and pain relief for 120 minutes. The authors determined the amount of gel the participants applied. RESULTS: The responders' rates (the primary efficacy parameter), defined as the percentage of participants who had an improvement in pain intensity as exhibited by a pain score reduction of at least one unit on the dental pain scale from baseline for two consecutive assessments any time between the five- and 20-minute points, were 87.3 percent, 80.7 percent and 70.4 percent, respectively, for 20 percent benzocaine gel, 10 percent benzocaine gel and vehicle gel. Both benzocaine gels were significantly (P ≤ .05) better than vehicle gel; the 20 percent benzocaine gel also was significantly (P ≤ .05) better than the 10 percent benzocaine gel. The mean amount of gel applied was 235.6 milligrams, with 88.2 percent of participants applying 400 mg or less. CONCLUSIONS: Both 10 percent and 20 percent benzocaine gels were more efficacious than the vehicle gel, and the 20 percent benzocaine gel was more efficacious than the 10 percent benzocaine gel. All treatments were well tolerated by participants. Practical Implications. Patients can use 10 percent and 20 percent benzocaine gels to temporarily treat toothache pain safely.