Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

Neuromechanical Differences between Pronated and Supinated Forearm Positions during Upper-Body Wingate Tests.

Arm-cycling is a versatile exercise modality with applications in both athletic enhancement and rehabilitation, yet the influence of forearm orientation remains understudied. Thus, this study aimed to investigate the impact of forearm position on upper-body arm-cycling Wingate tests. Fourteen adult males (27.3 ± 5.8 years) underwent bilateral assessments of handgrip strength in standing and seated positions, followed by pronated and supinated forward arm-cycling Wingate tests. Electromyography (EMG) was recorded from five upper-extremity muscles, including anterior deltoid, triceps brachii lateral head, biceps brachii, latissimus dorsi, and brachioradialis. Simultaneously, bilateral normal and propulsion forces were measured at the pedal-crank interface. Rate of perceived exertion (RPE), power output, and fatigue index were recorded post-test. The results showed that a pronated forearm position provided significantly (p < 0.05) higher normal and propulsion forces and triceps brachii muscle activation patterns during arm-cycling. No significant difference in RPE was observed between forearm positions (p = 0.17). A positive correlation was found between seated handgrip strength and peak power output during the Wingate test while pronated (dominant: p = 0.01, r = 0.55; non-dominant: p = 0.03, r = 0.49) and supinated (dominant: p = 0.03, r = 0.51; don-dominant: p = 0.04, r = 0.47). Fatigue changed the force and EMG profile during the Wingate test. In conclusion, this study enhances our understanding of forearm position's impact on upper-body Wingate tests. These findings have implications for optimizing training and performance strategies in individuals using arm-cycling for athletic enhancement and rehabilitation.

Methods to increase response to postal and electronic questionnaires.

BACKGROUND: Self-administered questionnaires are widely used to collect data in epidemiological research, but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of epidemiological research. OBJECTIVES: To identify effective strategies to increase response to postal and electronic questionnaires. SEARCH METHODS: We searched 14 electronic databases up to December 2021 and manually searched the reference lists of relevant trials and reviews. We contacted the authors of all trials or reviews to ask about unpublished trials; where necessary, we also contacted authors to confirm the methods of allocation used and to clarify results presented. SELECTION CRITERIA: Randomised trials of methods to increase response to postal or electronic questionnaires. We assessed the eligibility of each trial using pre-defined criteria. DATA COLLECTION AND ANALYSIS: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity amongst trial odds ratios using a Chi2 test and quantified the degree of inconsistency between trial results using the I2 statistic. MAIN RESULTS: Postal We found 670 eligible trials that evaluated over 100 different strategies of increasing response to postal questionnaires. We found substantial heterogeneity amongst trial results in half of the strategies. The odds of response almost doubled when: using monetary incentives (odds ratio (OR) 1.86; 95% confidence interval (CI) 1.73 to 1.99; heterogeneity I2 = 85%); using a telephone reminder (OR 1.96; 95% CI 1.03 to 3.74); and when clinical outcome questions were placed last (OR 2.05; 95% CI 1.00 to 4.24). The odds of response increased by about half when: using a shorter questionnaire (OR 1.58; 95% CI 1.40 to 1.78); contacting participants before sending questionnaires (OR 1.36; 95% CI 1.23 to 1.51; I2 = 87%); incentives were given with questionnaires (i.e. unconditional) rather than when given only after participants had returned their questionnaire (i.e. conditional on response) (OR 1.53; 95% CI 1.35 to 1.74); using personalised SMS reminders (OR 1.53; 95% CI 0.97 to 2.42); using a special (recorded) delivery service (OR 1.68; 95% CI 1.36 to 2.08; I2 = 87%); using electronic reminders (OR 1.60; 95% CI 1.10 to 2.33); using intensive follow-up (OR 1.69; 95% CI 0.93 to 3.06); using a more interesting/salient questionnaire (OR 1.73; 95% CI 1.12 to 2.66); and when mentioning an obligation to respond (OR 1.61; 95% CI 1.16 to 2.22). The odds of response also increased with: non-monetary incentives (OR 1.16; 95% CI 1.11 to 1.21; I2 = 80%); a larger monetary incentive (OR 1.24; 95% CI 1.15 to 1.33); a larger non-monetary incentive (OR 1.15; 95% CI 1.00 to 1.33); when a pen was included (OR 1.44; 95% CI 1.38 to 1.50); using personalised materials (OR 1.15; 95% CI 1.09 to 1.21; I2 = 57%); using a single-sided rather than a double-sided questionnaire (OR 1.13; 95% CI 1.02 to 1.25); using stamped return envelopes rather than franked return envelopes (OR 1.23; 95% CI 1.13 to 1.33; I2 = 69%), assuring confidentiality (OR 1.33; 95% CI 1.24 to 1.42); using first-class outward mailing (OR 1.11; 95% CI 1.02 to 1.21); and when questionnaires originated from a university (OR 1.32; 95% CI 1.13 to 1.54). The odds of response were reduced when the questionnaire included questions of a sensitive nature (OR 0.94; 95% CI 0.88 to 1.00). Electronic We found 88 eligible trials that evaluated over 30 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity amongst trial results in half of the strategies. The odds of response tripled when: using a brief letter rather than a detailed letter (OR 3.26; 95% CI 1.79 to 5.94); and when a picture was included in an email (OR 3.05; 95% CI 1.84 to 5.06; I2 = 19%). The odds of response almost doubled when: using monetary incentives (OR 1.88; 95% CI 1.31 to 2.71; I2 = 79%); and using a more interesting topic (OR 1.85; 95% CI 1.52 to 2.26). The odds of response increased by half when: using non-monetary incentives (OR 1.60; 95% CI 1.25 to 2.05); using shorter e-questionnaires (OR 1.51; 95% CI 1.06 to 2.16; I2 = 94%); and using a more interesting e-questionnaire (OR 1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third when: offering survey results as an incentive (OR 1.36; 95% CI 1.16 to 1.59); using a white background (OR 1.31; 95% CI 1.10 to 1.56); and when stressing the benefits to society of response (OR 1.38; 95% CI 1.07 to 1.78; I2 = 41%). The odds of response also increased with: personalised e-questionnaires (OR 1.24; 95% CI 1.17 to 1.32; I2 = 41%); using a simple header (OR 1.23; 95% CI 1.03 to 1.48); giving a deadline (OR 1.18; 95% CI 1.03 to 1.34); and by giving a longer time estimate for completion (OR 1.25; 95% CI 0.96 to 1.64). The odds of response were reduced when: "Survey" was mentioned in the e-mail subject (OR 0.81; 95% CI 0.67 to 0.97); when the email or the e-questionnaire was from a male investigator, or it included a male signature (OR 0.55; 95% CI 0.38 to 0.80); and by using university sponsorship (OR 0.84; 95%CI 0.69 to 1.01). The odds of response using a postal questionnaire were over twice those using an e-questionnaire (OR 2.33; 95% CI 2.25 to 2.42; I2 = 98%). Response also increased when: providing a choice of response mode (electronic or postal) rather than electronic only (OR 1.76 95% CI 1.67 to 1.85; I2 = 97%); and when administering the e-questionnaire by computer rather than by smartphone (OR 1.62 95% CI 1.36 to 1.94). AUTHORS' CONCLUSIONS: Researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this Cochrane review.

Psychological characteristics of developing excellence in talented female field hockey players.

Psychological Characteristics of Developing Excellence (PCDEs) are a range of psychological factors that play a key role in the realisation of potential. We examined PCDE profiles across a female national talent development field hockey programme in North America. Two-hundred-and-sixty-seven players completed the Psychological Characteristics of Developing Excellence Questionnaire version 2 (PCDEQ-2) prior to the competitive season. One-hundred-and-fourteen players were classified as juniors (under-18) and 153 as seniors (over-18). Eighty-five players were classified as non-selected (not-selected to their age-group national team), and 182 as selected (selected to their age-group national team). A MANOVA showed multivariate differences based on age, selection status and their interaction, within this already homogenous sample, suggesting that sub-groups within this sample vary depending on their overall PCDE profiles. ANOVA showed differences in imagery and active preparation, perfectionist tendencies and clinical indicators between juniors and seniors. Furthermore, differences in imagery and active preparation, and perfectionist tendencies, were observed between selected and non-selected players. Subsequently, four individual cases were identified for further analysis based on their multivariate distance to the average PCDE profile. The use of the PCDEQ-2 at group- and particularly at individual-levels seems an important tool to support athletes as they navigate their development journey.

Thunder road - whole-body vibration during road cycling, and the effect of different seatpost designs to minimise it.

Exposure to whole-body vibration (WBV) increases the risk of low back pain, spinal degeneration, and injury. Cycling can expose participants to WBV, but there are limited data available. This preliminary study quantified WBV in road cyclists in accordance with ISO 2631-1, and determined the efficacy of two seatposts designed to minimise vibration, compared to an aluminium alloy seatpost. Sensors were used to measure the root-mean-squared acceleration (arms), frequency-weighted arms based on an eight-hour reference period (A(8)), vibration dose value (VDV), and transmissibility. Exposures were also calculated using the root-sum-of-squares of the frequency-weighted arms in all three axes (A(8)rss and VDVrss). The mean±95% confidence interval A(8)rss and VDVrss across all tests was 0.58 ± 0.07 ms-2 and 37.19 ± 4.70 ms-1.75 respectively at the saddle, if and 0.49 ± 0.06 ms-2 and 24.31 ± 2.89 ms-1.75 respectively at the lumbar position. Occupational limits were exceeded with all seatposts, and there were no significant differences between them (p > 0.227). Road cycling results in substantial WBV, and there was no evidence that the seatposts designed to minimise vibrations successfully do so. Further research into the effect of cycling conditions and equipment on WBV would be valuable to both the research and cycling communities.

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic.

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s.

Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease.

Parkinson's disease primarily affects the central nervous system, but autopsy and small patient studies have revealed autonomic nervous system pathology in most cases. We looked for α-synuclein pathology in routinely acquired biopsies from patients and matched controls. Immunocytochemistry was performed and assessed blind to the clinical diagnoses. One hundred and seventeen gastrointestinal tissue samples from 62 patients, and 161 samples from 161 controls, were examined. Twelve biopsies from seven patients showed accumulation of α-synuclein within mucosal and submucosal nerve fibres, and ganglia, which was more extensive with an antibody to phosphorylated, than with an antibody to non-phosphorylated, α-synuclein. These included gastric, duodenal and colonic biopsies, and were taken up to 8 years prior to the onset of motor symptoms. All patients with positive biopsies had early autonomic symptoms and all controls were negative. This large scale study demonstrates that accumulation of α-synuclein in the gastrointestinal tract is a highly specific finding that could be used to confirm a clinical diagnosis of Parkinson's disease. We have shown that α-synuclein accumulation occurs prior to the onset of motor symptoms in the upper, as well as the lower gastrointestinal tract, remains present in serial biopsies until the onset of motor symptoms and is predominantly composed of phosphorylated α-synuclein. Accumulation of α-synuclein in the bowel therefore offers an accessible biomarker which allows further study of the early stages of the disease and could be of value in the assessment of disease modifying treatments.

The Effects of Load, Crank Position, and Sex on the Biomechanics and Performance during an Upper Body Wingate Anaerobic Test.

INTRODUCTION: The upper body Wingate Anaerobic Test (WAnT) is a 30-second maximal effort sprint against a set load (percentage of body mass). However, there is no consensus on the optimal load and no differential values for males and females, even when there are well-studied anatomical and physiological differences in muscle mass for the upper body. Our goal was to describe the effects of load, sex, and crank position on the kinetics, kinematics, and performance of the upper body WAnT. METHODS: Eighteen participants (9 females) performed three WAnTs at 3, 4, and 5% of body mass. Arm crank forces, 2D kinematics, and performance variables were recorded during each WAnT. RESULTS: Our results showed an increase of ~49% effective force, ~36% peak power, ~5° neck flexion, and ~ 30° shoulder flexion from 3-5% load (p < .05). Mean power and anaerobic capacity decreased by 15%, with no changes in fatigue index (p < .05). The positions of higher force efficiency were at 12 and 6 o'clock. The least force efficiency occurred at 3 o'clock (p < .05). Sex differences showed that males produced 97% more effective force and 109% greater mean power than females, with 11.7% more force efficiency (p < .001). Males had 16° more head/neck flexion than females, and females had greater elbow joint variability with 17° more wrist extension at higher loads. Males cycled ~32% faster at 3 vs 5% load with a 65% higher angular velocity than females. Grip strength, MVIC, mass, and height positively correlated with peak and mean power (p < .001). CONCLUSIONS: In conclusion, load, sex, and crank position have a significant impact on performance of the WAnT. These factors should be considered when developing and implementing an upper body WAnT.

CAL-Tutor: A HoloLens 2 Application for Training in Obstetric Sonography and User Motion Data Recording.

Obstetric ultrasound (US) training teaches the relationship between foetal anatomy and the viewed US slice to enable navigation to standardised anatomical planes (head, abdomen and femur) where diagnostic measurements are taken. This process is difficult to learn, and results in considerable inter-operator variability. We propose the CAL-Tutor system for US training based on a US scanner and phantom, where a model of both the baby and the US slice are displayed to the trainee in its physical location using the HoloLens 2. The intention is that AR guidance will shorten the learning curve for US trainees and improve spatial awareness. In addition to the AR guidance, we also record many data streams to assess user motion and the learning process. The HoloLens 2 provides eye gaze, head and hand position, ARToolkit and NDI Aurora tracking gives the US probe positions and an external camera records the overall scene. These data can provide a rich source for further analysis, such as distinguishing expert from novice motion. We have demonstrated the system in a sample of engineers. Feedback suggests that the system helps novice users navigate the US probe to the standard plane. The data capture is successful and initial data visualisations show that meaningful information about user behaviour can be captured. Initial feedback is encouraging and shows improved user assessment where AR guidance is provided.

Two controlled trials to increase participant retention in a randomized controlled trial of mobile phone-based smoking cessation support in the United Kingdom.

BACKGROUND: Loss to follow-up of trial participants represents a threat to research validity. To date, interventions designed to increase participants' awareness of benefits to society of completing follow-up, and the impact of a telephone call from a senior female clinician and researcher requesting follow-up have not been evaluated robustly. PURPOSE: Trial 1 aimed to evaluate the effect on trial follow-up of written information regarding the benefits of participation to society. Trial 2 aimed to evaluate the effect on trial follow-up of a telephone call from a senior female clinician and researcher. METHODS: Two single-blind randomized controlled trials were nested within a larger trial, Txt2stop. In Trial 1, participants were allocated using minimization to receive a refrigerator magnet and a text message emphasizing the benefits to society of completing follow-up, or to a control group receiving a simple reminder regarding follow-up. In Trial 2, participants were randomly allocated to receive a telephone call from a senior female clinician and researcher, or to a control group receiving standard Txt2stop follow-up procedures. RESULTS: Trial 1: 33.5% (327 of 976) of the intervention group and 33.8% (329 of 974) of the control group returned the questionnaire within 26 weeks of randomization, risk ratio (RR) 0.99; 95% confidence interval (CI) 0.88-1.12. In all, 83.3% (813 of 976) of the intervention group and 82.2% (801 of/974) of the control group sent back the questionnaire within 30 weeks of randomization, RR 1.01; 95% CI 0.97, 1.05. Trial 2: 31% (20 of 65) of the intervention group and 32% (20 of 62) of the control group completed trial follow-up, RR 0.93; 95%CI 0.44, 1.98. CONCLUSIONS: In presence of other methods to increase follow-up neither experimental method (refrigerator magnet and text message emphasizing participation's benefits to society nor a telephone call from study's principal investigator) increased participant follow-up in the Txt2stop trial.

Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.

Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.

Caffeine for the prevention of injuries and errors in shift workers.

BACKGROUND: Sleepiness leads to a deterioration in performance and attention, and is associated with an increased risk of injury. Jet lag and shift work disorder are circadian rhythm sleep disorders which result in sleepiness and can elevate injury risk. They create a need for individuals to operate at times which are different to those dictated by their circadian rhythms. Consequently there is also a need for interventions to help ensure that these persons can do so safely. Caffeine has a potential role in promoting alertness during times of desired wakefulness in persons with jet lag or shift work disorder, however its effects on injury and error are unclear. OBJECTIVES: To assess the effects of caffeine for preventing injuries caused by impaired alertness in persons with jet lag or shift work disorder. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, CINAHL, TRANSPORT (to July 2008); and PubMed databases (to April 2010). We also searched the Internet and checked reference lists of relevant papers. SELECTION CRITERIA: Randomised controlled trials investigating the effects of caffeine on injury, error or cognitive performance in people with jet lag or shift work disorder. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results and assessed full texts for inclusion. Data were extracted and risk of bias was assessed. Estimates of treatment effect (odds ratio and standardised mean difference (SMD)) and 95% confidence intervals (CI) were calculated and pooled using the fixed-effect model. MAIN RESULTS: Thirteen trials were included. None measured an injury outcome. Two trials measured error, and the remaining trials used neuropsychological tests to assess cognitive performance. The trials assessing the impact on errors found that caffeine significantly reduced the number of errors compared to placebo. The pooled effect estimates on performance by cognitive domain suggest that, when compared to placebo, caffeine improved concept formation and reasoning (SMD -0.41; 95% CI -1.04 to 0.23), memory (SMD -1.08; 95% CI -2.07 to -0.09), orientation and attention (SMD -0.55; 95% CI -0.83 to -0.27) and perception (SMD -0.77; 95% CI -1.73 to 0.20); although there was no beneficial effect on verbal functioning and language skills (SMD 0.18; 95% CI -0.50 to 0.87). One trial comparing the effects of caffeine with a nap found that there were significantly less errors made in the caffeine group. Other trials comparing caffeine with other active interventions (for example nap, bright light, modafinil) found no significant differences. There is a high risk of bias for the adequacy of allocation concealment and presence of selective outcome reporting amongst the trials. AUTHORS' CONCLUSIONS: Caffeine may be an effective intervention for improving performance in shift workers however, there are no trials from which we can assess its effect on injuries. The results largely originate from studies involving young participants under simulated conditions, and the extent to which the findings are generalisable to older workers and real world shift work is unclear. Based on the current evidence, there is no reason for healthy individuals who already use caffeine within recommended levels to improve their alertness to stop doing so. The assessment of the relative effects of caffeine to other potential countermeasures should be a focus of future research.

Ultrasound 3D reconstruction of malignant masses in robotic-assisted partial nephrectomy using the PAF rail system: a comparison study.

PURPOSE: In robotic-assisted partial nephrectomy (RAPN), the use of intraoperative ultrasound (IOUS) helps to localise and outline the tumours as well as the blood vessels within the kidney. The aim of this work is to evaluate the use of the pneumatically attachable flexible (PAF) rail system for US 3D reconstruction of malignant masses in RAPN. The PAF rail system is a novel device developed and previously presented by the authors to enable track-guided US scanning. METHODS: We present a comparison study between US 3D reconstruction of masses based on: the da Vinci Surgical System kinematics, single- and stereo-camera tracking of visual markers embedded on the probe. An US-realistic kidney phantom embedding a mass is used for testing. A new design for the US probe attachment to enhance the performance of the kinematic approach is presented. A feature extraction algorithm is proposed to detect the margins of the targeted mass in US images. RESULTS: To evaluate the performance of the investigated approaches the resulting 3D reconstructions have been compared to a CT scan of the phantom. The data collected indicates that single camera reconstruction outperformed the other approaches, reconstructing with a sub-millimetre accuracy the targeted mass. CONCLUSIONS: This work demonstrates that the PAF rail system provides a reliable platform to enable accurate US 3D reconstruction of masses in RAPN procedures. The proposed system has also the potential to be employed in other surgical procedures such as hepatectomy or laparoscopic liver resection.

Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening.

trans-Sialidase from Trypanosoma cruzi (TcTS) has emerged as a potential drug target for treatment of Chagas disease. Here, we report the results of virtual screening for the discovery of novel TcTS inhibitors, which targeted both the sialic acid and sialic acid acceptor sites of this enzyme. A library prepared from the Evotec database of commercially available compounds was screened using the molecular docking program GOLD, following the application of drug-likeness filters. Twenty-three compounds selected from the top-scoring ligands were purchased and assayed using a fluorimetric assay. Novel inhibitor scaffolds, with IC(50) values in the submillimolar range were discovered. The 3-benzothiazol-2-yl-4-phenyl-but-3-enoic acid scaffold was studied in more detail, and TcTS inhibition was confirmed by an alternative sialic acid transfer assay. Attempts to obtain crystal structures of these compounds with TcTS proved unsuccessful but provided evidence of ligand binding at the active site.

Interventions for preventing injuries caused by impaired alertness in individuals with jet lag and shift work disorder.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of interventions for preventing injuries caused by impaired alertness in persons with jet lag or shift work disorder.

Methods to increase response to postal and electronic questionnaires.

BACKGROUND: Postal and electronic questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of health research. OBJECTIVES: To identify effective strategies to increase response to postal and electronic questionnaires. SEARCH STRATEGY: We searched 14 electronic databases to February 2008 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, we also contacted authors to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria. SELECTION CRITERIA: Randomised controlled trials of methods to increase response to postal or electronic questionnaires. DATA COLLECTION AND ANALYSIS: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity among trial odds ratios using a Chi(2) test and the degree of inconsistency between trial results was quantified using the I(2) statistic. MAIN RESULTS: PostalWe found 481 eligible trials. The trials evaluated 110 different ways of increasing response to postal questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.87; 95% CI 1.73 to 2.04; heterogeneity P < 0.00001, I(2) = 84%), recorded delivery (1.76; 95% CI 1.43 to 2.18; P = 0.0001, I(2) = 71%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08; 95% CI 1.27 to 7.44) and a more interesting questionnaire topic (2.00; 95% CI 1.32 to 3.04; P = 0.06, I(2) = 80%). The odds of response were substantially higher with pre-notification (1.45; 95% CI 1.29 to 1.63; P < 0.00001, I(2) = 89%), follow-up contact (1.35; 95% CI 1.18 to 1.55; P < 0.00001, I(2) = 76%), unconditional incentives (1.61; 1.36 to 1.89; P < 0.00001, I(2) = 88%), shorter questionnaires (1.64; 95% CI 1.43 to 1.87; P < 0.00001, I(2) = 91%), providing a second copy of the questionnaire at follow up (1.46; 95% CI 1.13 to 1.90; P < 0.00001, I(2) = 82%), mentioning an obligation to respond (1.61; 95% CI 1.16 to 2.22; P = 0.98, I(2) = 0%) and university sponsorship (1.32; 95% CI 1.13 to 1.54; P < 0.00001, I(2) = 83%). The odds of response were also increased with non-monetary incentives (1.15; 95% CI 1.08 to 1.22; P < 0.00001, I(2) = 79%), personalised questionnaires (1.14; 95% CI 1.07 to 1.22; P < 0.00001, I(2) = 63%), use of hand-written addresses (1.25; 95% CI 1.08 to 1.45; P = 0.32, I(2) = 14%), use of stamped return envelopes as opposed to franked return envelopes (1.24; 95% CI 1.14 to 1.35; P < 0.00001, I(2) = 69%), an assurance of confidentiality (1.33; 95% CI 1.24 to 1.42) and first class outward mailing (1.11; 95% CI 1.02 to 1.21; P = 0.78, I(2) = 0%). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94; 95% CI 0.88 to 1.00; P = 0.51, I(2) = 0%).ElectronicWe found 32 eligible trials. The trials evaluated 27 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were increased by more than a half using non-monetary incentives (1.72; 95% CI 1.09 to 2.72; heterogeneity P < 0.00001, I(2) = 95%), shorter e-questionnaires (1.73; 1.40 to 2.13; P = 0.08, I(2) = 68%), including a statement that others had responded (1.52; 95% CI 1.36 to 1.70), and a more interesting topic (1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third using a lottery with immediate notification of results (1.37; 95% CI 1.13 to 1.65), an offer of survey results (1.36; 95% CI 1.15 to 1.61), and using a white background (1.31; 95% CI 1.10 to 1.56). The odds of response were also increased with personalised e-questionnaires (1.24; 95% CI 1.17 to 1.32; P = 0.07, I(2) = 41%), using a simple header (1.23; 95% CI 1.03 to 1.48), using textual representation of response categories (1.19; 95% CI 1.05 to 1.36), and giving a deadline (1.18; 95% CI 1.03 to 1.34). The odds of response tripled when a picture was included in an e-mail (3.05; 95% CI 1.84 to 5.06; P = 0.27, I(2) = 19%). The odds of response were reduced when "Survey" was mentioned in the e-mail subject line (0.81; 95% CI 0.67 to 0.97; P = 0.33, I(2) = 0%), and when the e-mail included a male signature (0.55; 95% CI 0.38 to 0.80; P = 0.96, I(2) = 0%). AUTHORS' CONCLUSIONS: Health researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this systematic review.

Discovery of a novel warhead against beta-secretase through fragment-based lead generation.

Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.

Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.

Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 microM) and 6c (IC50 = 24 microM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).

Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.

Postoperative calculation of acetabular cup position using 2-D-3-D registration.

A method to accurately measure the position and orientation of an acetabular cup implant from postoperative X-rays has been designed and validated. The method uses 2-D-3-D registration to align both the prosthesis and the preoperative computed tomography (CT) volume to the X-ray image. This allows the position of the implant to be calculated with respect to a CT-based surgical plan. Experiments have been carried out using ten sets of patient data. A conventional plain-film measurement technique was also investigated. A gold standard implant position and orientation was calculated using postoperative CT. Results show our method to be significantly more accurate than the plain-film method for calculating cup anteversion. Cup orientation and position could be measured to within a mean absolute error of 1.4 mm or degrees.