Non-invasive methods of monitoring Fe3O4 magnetic nanoparticle toxicity in human liver HepaRG cells using impedance biosensing and Coherent anti-Stokes Raman spectroscopic (CARS) microscopy.

Functionalized nanoparticles have been developed for use in nanomedicines for treating life threatening diseases including various cancers. To ensure safe use of these new nanoscale reagents, various assays for biocompatibility or cytotoxicity in vitro using cell lines often serve as preliminary assessments prior to in vivo animal testing. However, many of these assays were designed for soluble, colourless materials and may not be suitable for coloured, non-transparent nanoparticles. Moreover, cell lines are not always representative of mammalian organs in vivo. In this work, we use non-invasive impedance sensing methods with organotypic human liver HepaRG cells as a model to test the toxicity of PEG-Fe3O4 magnetic nanoparticles. We also use Coherent anti-Stokes Raman Spectroscopic (CARS) microscopy to monitor the formation of lipid droplets as a parameter to the adverse effect on the HepaRG cell model. The results were also compared with two commercial testing kits (PrestoBlue and ATP) for cytotoxicity. The results suggested that the HepaRG cell model can be a more realistic model than commercial cell lines while use of impedance monitoring of Fe3O4 nanoparticles circumventing the uncertainties due to colour assays. These methods can play important roles for scientists driving towards the 3Rs principle - Replacement, Reduction and Refinement.

Between Two Rocks and in a Hard Place: Reflecting on the Biomechanical Basis of Shoulder Occupational Musculoskeletal Disorders.

OBJECTIVE: The aim was to review the biomechanical origins of occupational shoulder damage, while considering the complexity of shoulder mechanics and musculoskeletal consequences of diverse task demands. BACKGROUND: Accessible measures of physical exposures are the primary focus of occupational shoulder assessments and analyses. This approach has led to guidelines and intervention strategies that are often inadequate for mitigating shoulder disorders amongst the complexity of modern workplace demands. Integration of complex shoulder mechanics into occupational assessments, analyses, and interventions is critical for reducing occupational shoulder injury risk. METHOD: This narrative review describes shoulder biomechanics in the context of common injury mechanisms and consequent injuries, with a particular focus on subacromial impingement syndrome. Several modulators of shoulder injury risk are reviewed, including fatigue, overhead work, office ergonomics considerations, and pushing and pulling task configurations. RESULTS: Relationships between work requirements, muscular demands, fatigue, and biomechanical tissue loads exist. This review highlights that consideration of specific workplace factors should be integrated with our knowledge of the intricate arrangement and interpersonal variability of the shoulder complex to proactively evaluate occupational shoulder demands and exposures. CONCLUSION: A standard method for evaluating shoulder muscle exposures during workplace tasks does not exist. An integrated approach is critical for improved work design and prevention of shoulder tissue damage and accompanying disability. APPLICATION: This review is particularly relevant for researchers and practitioners, providing guidance for work design and evaluation for shoulder injury prevention by understanding the importance of the unique and complex mechanics of the shoulder.

Single-incision mini-slings versus standard synthetic mid-urethral slings for surgical treatment of stress urinary incontinence in women: The SIMS RCT.

BACKGROUND: Stress urinary incontinence is the most common type of urinary incontinence in premenopausal women. Until recently, synthetic mid-urethral slings (mesh/tape) were the standard surgical treatment, if conservative management failed. Adjustable anchored single-incision mini-slings are newer, use less mesh and may reduce perioperative morbidity, but it is unclear how their success rates and safety compare with those of standard tension-free mid-urethral slings. OBJECTIVE: The objective was to compare tension-free standard mid-urethral slings with adjustable anchored single-incision mini-slings among women with stress urinary incontinence requiring surgical intervention, in terms of patient-reported effectiveness, health-related quality of life, safety and cost-effectiveness. DESIGN: This was a pragmatic non-inferiority randomised controlled trial. Allocation was by remote web-based randomisation (1 : 1 ratio). SETTING: The trial was set in 21 UK hospitals. PARTICIPANTS: Participants were women aged ≥ 18 years with predominant stress urinary incontinence, undergoing a mid-urethral sling procedure. INTERVENTIONS: Single-incision mini-slings, compared with standard mid-urethral slings. MAIN OUTCOME MEASURES: The primary outcome was patient-reported success rates on the Patient Global Impression of Improvement scale at 15 months post randomisation (≈ 1 year post surgery), with success defined as outcomes of 'very much improved' or 'much improved'. The primary economic outcome was incremental cost per quality-adjusted life-year gained. Secondary outcomes were adverse events, impact on other urinary symptoms, quality of life and sexual function. RESULTS: A total of 600 participants were randomised. At 15 months post randomisation, adjustable anchored single-incision mini-slings were non-inferior to tension-free standard mid-urethral slings at the 10% margin for the primary outcome [single-incision mini-sling 79% (212/268) vs. standard mid-urethral sling 76% (189/250), risk difference 4.6, 95% confidence interval -2.7 to 11.8; p non-inferiority < 0.001]. Similarly, at 3 years' follow-up, patient-reported success rates in the single-incision mini-sling group were non-inferior to those of the standard mid-urethral sling group at the 10% margin [single-incision mini-sling 72% (177/246) vs. standard mid-urethral sling 67% (157/235), risk difference 5.7, 95% confidence interval -1.3 to 12.8; p non-inferiority < 0.001]. Tape/mesh exposure rates were higher for single-incision mini-sling participants, with 3.3% (9/276) [compared with 1.9% (5/261) in the standard mid-urethral sling group] reporting tape exposure over the 3 years of follow-up. The rate of groin/thigh pain was slightly higher in the single-incision mini-sling group at 15 months [single-incision mini-sling 15% (41/276) vs. standard mid-urethral sling 12% (31/261), risk difference 3.0%, 95% confidence interval -1.1% to 7.1%]; however, by 3 years, the rate of pain was slightly higher among the standard mid-urethral sling participants [single-incision mini-sling 14% (39/276) vs. standard mid-urethral sling 15% (39/261), risk difference -0.8, 95% confidence interval -4.1 to 2.5]. At the 3-year follow-up, quality of life and sexual function outcomes were similar in both groups: for the International Consultation on Incontinence Questionnaire Lower Urinary Tract Symptoms Quality of Life, the mean difference in scores was -1.1 (95% confidence interval -3.1 to 0.8; p = 0.24), and for the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, International Urogynecological Association-Revised, it was 0 (95% confidence interval -0.1, 0.1; p = 0.92). However, more women in the single-incision mini-sling group reported dyspareunia [12% (17/145), compared with 4.8% (7/145) in the standard mid-urethral sling group, risk difference 7.0%, 95% confidence interval 1.9% to 12.1%]. The base-case economics results showed no difference in costs (-£6, 95% confidence interval -£228 to £208) or quality-adjusted life-years (0.005, 95% confidence interval -0.068 to 0.073) between the groups. There is a 56% probability that single-incision mini-slings will be considered cost-effective at the £20,000 willingness-to-pay threshold value for a quality-adjusted life-year. LIMITATIONS: Follow-up data beyond 3 years post randomisation are not available to inform longer-term safety and cost-effectiveness. CONCLUSIONS: Single-incision mini-slings were non-inferior to standard mid-urethral slings in patient-reported success rates at up to 3 years' follow-up. FUTURE WORK: Success rates, adverse events, retreatment rates, symptoms, and quality-of-life scores at 10 years' follow-up will help inform long-term effectiveness. TRIAL REGISTRATION: This trial was registered as ISRCTN93264234. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 47. See the NIHR Journals Library website for further project information.

Stress urinary incontinence, the involuntary leakage of urine, is a common and distressing condition, particularly for women aged > 40 years. In the UK, it is estimated that 6 million (40%) of this age group have symptoms bothersome enough for doctors to investigate. It causes embarrassment, low self-esteem and even social isolation. Standard surgical treatment used to be a mid-urethral sling made of mesh, inserted, in most cases, under general anaesthetic. Recently, a single-incision mini-sling, using less mesh, has been available under local anaesthetic. A number of small studies have shown that mini-slings have similar success rates to those of standard slings, necessitate shorter hospital stays and are less painful immediately after surgery. However, these results were uncertain and the potential longer-term benefits and disadvantages of both types of sling treatments were unknown. We compared the two types of sling treatments in a randomised trial of 600 women to see if they were equally effective. Success was measured by asking women to report on their symptoms and experiences. We also collected information on safety, quality of life, sexual function, and costs to women and the NHS. Every participant had an equal chance of starting treatment with the standard sling or the mini-sling. Participants were followed up for 3 years. Women allocated to each treatment reported similar success rates, quality of life and sexual function at 3 years. Women who received the new mini-sling had more mesh exposure (3% for the mini-sling vs. 2% for the standard sling) and were more likely to report pain during intercourse (12% vs. 5%) than women who received the standard sling. Both treatments had similar costs. Follow-up to 10 years is under way to establish the long-term benefits and disadvantages.

Photodynamic versus white-light-guided resection of first-diagnosis non-muscle-invasive bladder cancer: PHOTO RCT.

BACKGROUND: Around 7500 people are diagnosed with non-muscle-invasive bladder cancer in the UK annually. Recurrence following transurethral resection of bladder tumour is common, and the intensive monitoring schedule required after initial treatment has associated costs for patients and the NHS. In photodynamic diagnosis, before transurethral resection of bladder tumour, a photosensitiser that is preferentially absorbed by tumour cells is instilled intravesically. Transurethral resection of bladder tumour is then conducted under blue light, causing the photosensitiser to fluoresce. Photodynamic diagnosis-guided transurethral resection of bladder tumour offers better diagnostic accuracy than standard white-light-guided transurethral resection of bladder tumour, potentially reducing the chance of subsequent recurrence. OBJECTIVE: The objective was to assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis-guided transurethral resection of bladder tumour. DESIGN: This was a multicentre, pragmatic, open-label, parallel-group, non-masked, superiority randomised controlled trial. Allocation was by remote web-based service, using a 1 : 1 ratio and a minimisation algorithm balanced by centre and sex. SETTING: The setting was 22 NHS hospitals. PARTICIPANTS: Patients aged ≥ 16 years with a suspected first diagnosis of high-risk non-muscle-invasive bladder cancer, no contraindications to photodynamic diagnosis and written informed consent were eligible. INTERVENTIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour and standard white-light cystoscopy transurethral resection of bladder tumour. MAIN OUTCOME MEASURES: The primary clinical outcome measure was the time to recurrence from the date of randomisation to the date of pathologically proven first recurrence (or intercurrent bladder cancer death). The primary health economic outcome was the incremental cost per quality-adjusted life-year gained at 3 years. RESULTS: We enrolled 538 participants from 22 UK hospitals between 11 November 2014 and 6 February 2018. Of these, 269 were allocated to photodynamic diagnosis and 269 were allocated to white light. A total of 112 participants were excluded from the analysis because of ineligibility (n = 5), lack of non-muscle-invasive bladder cancer diagnosis following transurethral resection of bladder tumour (n = 89) or early cystectomy (n = 18). In total, 209 photodynamic diagnosis and 217 white-light participants were included in the clinical end-point analysis population. All randomised participants were included in the cost-effectiveness analysis. Over a median follow-up period of 21 months for the photodynamic diagnosis group and 22 months for the white-light group, there were 86 recurrences (3-year recurrence-free survival rate 57.8%, 95% confidence interval 50.7% to 64.2%) in the photodynamic diagnosis group and 84 recurrences (3-year recurrence-free survival rate 61.6%, 95% confidence interval 54.7% to 67.8%) in the white-light group (hazard ratio 0.94, 95% confidence interval 0.69 to 1.28; p = 0.70). Adverse event frequency was low and similar in both groups [12 (5.7%) in the photodynamic diagnosis group vs. 12 (5.5%) in the white-light group]. At 3 years, the total cost was £12,881 for photodynamic diagnosis-guided transurethral resection of bladder tumour and £12,005 for white light. There was no evidence of differences in the use of health services or total cost at 3 years. At 3 years, the quality-adjusted life-years gain was 2.094 in the photodynamic diagnosis transurethral resection of bladder tumour group and 2.087 in the white light group. The probability that photodynamic diagnosis-guided transurethral resection of bladder tumour was cost-effective was never > 30% over the range of society's cost-effectiveness thresholds. LIMITATIONS: Fewer patients than anticipated were correctly diagnosed with intermediate- to high-risk non-muscle-invasive bladder cancer before transurethral resection of bladder tumour and the ratio of intermediate- to high-risk non-muscle-invasive bladder cancer was higher than expected, reducing the number of observed recurrences and the statistical power. CONCLUSIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour did not reduce recurrences, nor was it likely to be cost-effective compared with white light at 3 years. Photodynamic diagnosis-guided transurethral resection of bladder tumour is not supported in the management of primary intermediate- to high-risk non-muscle-invasive bladder cancer. FUTURE WORK: Further work should include the modelling of appropriate surveillance schedules and exploring predictive and prognostic biomarkers. TRIAL REGISTRATION: This trial is registered as ISRCTN84013636. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Around 7500 people are diagnosed with early-stage bladder cancer in the UK each year. Early bladder cancer is contained within the bladder and has not yet invaded the bladder's muscle wall or spread elsewhere in the body. The cancer will return (recur) in around half of people after initial treatment and they have to attend hospital for regular check-ups, with costs to both them and the NHS. The first step in treating early bladder cancer is surgery to remove the tumour. This surgery is normally performed under white light. Photodynamic diagnosis is a new technique in which a liquid is put into the patient's bladder before surgery and a blue light is used during the operation. This causes the bladder cancer to fluoresce so that it can be seen more easily by the surgeon. The Photodynamic versus white-light-guided resection of first diagnosis non-muscle-invasive bladder cancer ( PHOTO ) trial aimed to find out whether or not using photodynamic diagnosis at initial surgery would reduce how often the cancer recurred and whether or not this could reduce the cost of treating early bladder cancer. A total of 538 people with early bladder cancer who had a medium to high chance of their cancer returning after treatment were enrolled in the PHOTO trial. They were included in one of two treatment groups, at random: 269 had photodynamic surgery and 269 had standard white-light surgery. People in both groups were monitored regularly for any recurrences, with further treatment as appropriate. After 3 years, 4 out of 10 people in each group had a recurrence of their bladder cancer. We found no difference between the treatment groups in the number of people with recurrences. We found no evidence of a benefit to patients, and the total costs of photodynamic surgery were higher than those of standard white light. We therefore recommend that it is no longer used in the treatment of this group of patients.

Synthetic sling or artificial urinary sphincter for men with urodynamic stress incontinence after prostate surgery: the MASTER non-inferiority RCT.

BACKGROUND: Stress urinary incontinence is common in men after prostate surgery and can be difficult to improve. Implantation of an artificial urinary sphincter is the most common surgical procedure for persistent stress urinary incontinence, but it requires specialist surgical skills, and revisions may be necessary. In addition, the sphincter is relatively expensive and its operation requires adequate patient dexterity. New surgical approaches include the male synthetic sling, which is emerging as a possible alternative. However, robust comparable data, derived from randomised controlled trials, on the relative safety and efficacy of the male synthetic sling and the artificial urinary sphincter are lacking. OBJECTIVE: We aimed to compare the clinical effectiveness and cost-effectiveness of the male synthetic sling with those of the artificial urinary sphincter surgery in men with persistent stress urinary incontinence after prostate surgery. DESIGN: This was a multicentre, non-inferiority randomised controlled trial, with a parallel non-randomised cohort and embedded qualitative component. Randomised controlled trial allocation was carried out by remote web-based randomisation (1 : 1), minimised on previous prostate surgery (radical prostatectomy or transurethral resection of the prostate), radiotherapy (or not, in relation to prostate surgery) and centre. Surgeons and participants were not blind to the treatment received. Non-randomised cohort allocation was participant and/or surgeon preference. SETTING: The trial was set in 28 UK urological centres in the NHS. PARTICIPANTS: Participants were men with urodynamic stress incontinence after prostate surgery for whom surgery was deemed appropriate. Exclusion criteria included previous sling or artificial urinary sphincter surgery, unresolved bladder neck contracture or urethral stricture after prostate surgery, and an inability to give informed consent or complete trial documentation. INTERVENTIONS: We compared male synthetic sling with artificial urinary sphincter. MAIN OUTCOME MEASURES: The clinical primary outcome measure was men's reports of continence (assessed from questions 3 and 4 of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form) at 12 months post randomisation (with a non-inferiority margin of 15%). The primary economic outcome was cost-effectiveness (assessed as the incremental cost per quality-adjusted life-year at 24 months post randomisation). RESULTS: In total, 380 men were included in the randomised controlled trial (n = 190 in each group), and 99 out of 100 men were included in the non-randomised cohort. In terms of continence, the male sling was non-inferior to the artificial urinary sphincter (intention-to-treat estimated absolute risk difference -0.034, 95% confidence interval -0.117 to 0.048; non-inferiority p = 0.003), indicating a lower success rate in those randomised to receive a sling, but with a confidence interval excluding the non-inferiority margin of -15%. In both groups, treatment resulted in a reduction in incontinence symptoms (as measured by the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form). Between baseline and 12 months' follow-up, the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score fell from 16.1 to 8.7 in the male sling group and from 16.4 to 7.5 in the artificial urinary sphincter group (mean difference for the time point at 12 months 1.30, 95% confidence interval 0.11 to 2.49; p = 0.032). The number of serious adverse events was small (male sling group, n = 8; artificial urinary sphincter group, n = 15; one man in the artificial urinary sphincter group experienced three serious adverse events). Quality-of-life scores improved and satisfaction was high in both groups. Secondary outcomes that showed statistically significant differences favoured the artificial urinary sphincter over the male sling. Outcomes of the non-randomised cohort were similar. The male sling cost less than the artificial sphincter but was associated with a smaller quality-adjusted life-year gain. The incremental cost-effectiveness ratio for male slings compared with an artificial urinary sphincter suggests that there is a cost saving of £425,870 for each quality-adjusted life-year lost. The probability that slings would be cost-effective at a £30,000 willingness-to-pay threshold for a quality-adjusted life-year was 99%. LIMITATIONS: Follow-up beyond 24 months is not available. More specific surgical/device-related pain outcomes were not included. CONCLUSIONS: Continence rates improved from baseline, with the male sling non-inferior to the artificial urinary sphincter. Symptoms and quality of life significantly improved in both groups. Men were generally satisfied with both procedures. Overall, secondary and post hoc analyses favoured the artificial urinary sphincter over the male sling. FUTURE WORK: Participant reports of any further surgery, satisfaction and quality of life at 5-year follow-up will inform longer-term outcomes. Administration of an additional pain questionnaire would provide further information on pain levels after both surgeries. TRIAL REGISTRATION: This trial is registered as ISRCTN49212975. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 36. See the NIHR Journals Library website for further project information.

Leakage of urine associated with physical exertion (e.g. sporting activities, sneezing or coughing) is common in men who have undergone prostate surgery, but it is difficult to improve. Many men still leak urine 12 months after their prostate surgery and may continue to wear protective pads or sheaths. The most common operation to improve incontinence is implantation of an artificial urinary sphincter. An artificial urinary sphincter is an inflatable cuff that is placed around the urethra, the tube that drains urine from the bladder. The cuff is inflated and compresses the urethra to prevent leaking. When the man needs to pass urine, he must deflate the cuff by squeezing a pump placed in his scrotum, which releases the compression on the urethra and allows the bladder to empty. Recently, a new device, the male sling (made from non-absorbable plastic mesh), has been developed. The sling, which is surgically inserted under the urethra, supports the bladder, but, in contrast to the artificial sphincter, it does not need to be deactivated by a pump and, therefore, the patient does not need to do anything to operate it. A sling is also easier for the surgeon to insert than a sphincter. However, in some men, the sling does not provide enough improvement in incontinence symptoms and another operation, to place an artificial urinary sphincter, is needed. The aim of this study was to determine if the male sling was as effective as the artificial urinary sphincter in treating men with bothersome incontinence after prostate surgery. The study took the form of a randomised controlled trial (the gold standard and most reliable way to compare treatments) in which men were randomised (allocated at random to one of two groups using a computer) to either a male sling or an artificial urinary sphincter operation. We asked men how they got on in the first 2 years after their operation. Regardless of which operation they had, incontinence and quality of life significantly improved and complications were rare. A small number of men did require another operation to improve their incontinence, and it was more likely that an artificial urinary sphincter was needed, rather than another sling operation, if a male sling was not successful. Satisfaction was high in both groups, but it was significantly higher in the artificial urinary sphincter group than in the male sling group. Those who received a male sling were less likely than those who received an artificial urinary sphincter to say that they would recommend their surgery to a friend.

Assessment of Walking Speed and Distance Post-Stroke Increases After Providing a Theory-Based Toolkit.

BACKGROUND AND PURPOSE: While underutilized, poststroke administration of the 10-m walk test (10mWT) and 6-minute walk test (6MWT) can improve care and is considered best practice. We aimed to evaluate provision of a toolkit designed to increase use of these tests by physical therapists (PTs). METHODS: In a before-and-after study, 54 PTs and professional leaders in 9 hospitals were provided a toolkit and access to a clinical expert over a 5-month period. The toolkit comprised a guide, smartphone app, and video, and described how to set up walkways, implement learning sessions, administer walk tests, and interpret and apply test results clinically. The proportion of hospital visits for which each walk test score was documented at least once (based on abstracted health records of ambulatory patients) were compared over 8-month periods pre- and post-intervention using generalized mixed models. RESULTS: Data from 347 and 375 pre- and postintervention hospital visits, respectively, were analyzed. Compared with preintervention, the odds of implementing the 10mWT were 12 times greater (odds ratio [OR] = 12.4, 95% confidence interval [CI] 5.8, 26.3), and of implementing the 6MWT were approximately 4 times greater (OR = 3.9, 95% CI 2.3, 6.7), post-intervention, after adjusting for hospital setting, ambulation ability, presence of aphasia and cognitive impairment, and provider-level clustering. Unadjusted change in the percentage of visits for which the 10mWT/6MWT was documented at least once was smallest in acute care settings (2.0/3.8%), and largest in inpatient and outpatient rehabilitation settings (28.0/19.9% and 29.4/23.4%, respectively). DISCUSSION AND CONCLUSIONS: Providing a comprehensive toolkit to hospitals with professional leaders likely contributed to increasing 10mWT and 6MWT administration during inpatient and outpatient stroke rehabilitation.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A390 ).

Shockwave lithotripsy compared with ureteroscopic stone treatment for adults with ureteric stones: the TISU non-inferiority RCT.

BACKGROUND: Urinary stone disease affects 2-3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient's quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention. The two standard interventions are shockwave lithotripsy and ureteroscopic stone treatment. Both treatments are effective, but they differ in terms of invasiveness, anaesthetic requirement, treatment setting, number of procedures, complications, patient-reported outcomes and cost. There is uncertainty around which is the more clinically effective and cost-effective treatment. OBJECTIVES: To determine if shockwave lithotripsy is clinically effective and cost-effective compared with ureteroscopic stone treatment in adults with ureteric stones who are judged to require active intervention. DESIGN: A pragmatic, multicentre, non-inferiority, randomised controlled trial of shockwave lithotripsy as a first-line treatment option compared with primary ureteroscopic stone treatment for ureteric stones. SETTING: Urology departments in 25 NHS hospitals in the UK. PARTICIPANTS: Adults aged ≥ 16 years presenting with a single ureteric stone in any segment of the ureter, confirmed by computerised tomography, who were able to undergo either shockwave lithotripsy or ureteroscopic stone treatment and to complete trial procedures. INTERVENTION: Eligible participants were randomised 1 : 1 to shockwave lithotripsy (up to two sessions) or ureteroscopic stone treatment. MAIN OUTCOME MEASURES: The primary clinical outcome measure was resolution of the stone episode (stone clearance), which was operationally defined as 'no further intervention required to facilitate stone clearance' up to 6 months from randomisation. This was determined from 8-week and 6-month case report forms and any additional hospital visit case report form that was completed by research staff. The primary economic outcome measure was the incremental cost per quality-adjusted life-year gained at 6 months from randomisation. We estimated costs from NHS resources and calculated quality-adjusted life-years from participant completion of the EuroQol-5 Dimensions, three-level version, at baseline, pre intervention, 1 week post intervention and 8 weeks and 6 months post randomisation. RESULTS: In the shockwave lithotripsy arm, 67 out of 302 (22.2%) participants needed further treatment. In the ureteroscopic stone treatment arm, 31 out of 302 (10.3%) participants needed further treatment. The absolute risk difference was 11.4% (95% confidence interval 5.0% to 17.8%); the upper bound of the 95% confidence interval ruled out the prespecified margin of non-inferiority (which was 20%). The mean quality-adjusted life-year difference (shockwave lithotripsy vs. ureteroscopic stone treatment) was -0.021 (95% confidence interval 0.033 to -0.010) and the mean cost difference was -£809 (95% confidence interval -£1061 to -£551). The probability that shockwave lithotripsy is cost-effective is 79% at a threshold of society's willingness to pay for a quality-adjusted life-year of £30,000. The CEAC is derived from the joint distribution of incremental costs and incremental effects. Most of the results fall in the south-west quadrant of the cost effectiveness plane as SWL always costs less but is less effective. LIMITATIONS: A limitation of the trial was low return and completion rates of patient questionnaires. The study was initially powered for 500 patients in each arm; however, the total number of patients recruited was only 307 and 306 patients in the ureteroscopic stone treatment and shockwave lithotripsy arms, respectively. CONCLUSIONS: Patients receiving shockwave lithotripsy needed more further interventions than those receiving primary ureteroscopic retrieval, although the overall costs for those receiving the shockwave treatment were lower. The absolute risk difference between the two clinical pathways (11.4%) was lower than expected and at a level that is acceptable to clinicians and patients. The shockwave lithotripsy pathway is more cost-effective in an NHS setting, but results in lower quality of life. FUTURE WORK: (1) The generic health-related quality-of-life tools used in this study do not fully capture the impact of the various treatment pathways on patients. A condition-specific health-related quality-of-life tool should be developed. (2) Reporting of ureteric stone trials would benefit from agreement on a core outcome set that would ensure that future trials are easier to compare. TRIAL REGISTRATION: This trial is registered as ISRCTN92289221. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 19. See the NIHR Journals Library website for further project information.

Approximately 1 in 20 people suffers from kidney stones that pass down the urine drainage tube (ureter) into the urinary bladder and cause episodes of severe pain (ureteric colic). People with ureteric colic attend hospital for pain relief and diagnosis. Although most stones smaller than 10 mm eventually reach the bladder and are passed during urination, some get stuck and have to be removed using telescopic surgery (called ureteroscopic stone treatment) or shockwave therapy (called shockwave lithotripsy). Ureteroscopic stone treatment involves passing a telescope-containing instrument through the bladder and into the ureter to fragment and/or remove the stone. This is usually carried out under general anaesthetic as a day case. For shockwave lithotripsy, the patient lies flat on a couch and the apparatus underneath them generates shockwaves that pass through the skin to the ureter and break the stones into smaller fragments, which can be passed naturally in the urine. This involves using X-ray or ultrasound to locate the stone, but can be carried out on an outpatient basis and without general anaesthetic. Telescopic surgery is known to be more successful at removing stones after just one treatment, but it requires more time in hospital and has a higher risk of complications than shockwave lithotripsy (however, shockwave lithotripsy may require more than one session of treatment). Our study, the Therapeutic Interventions for Stones of the Ureter trial, was designed to establish if treatment for ureteric colic should start with telescopic surgery or shockwave therapy. Over 600 NHS patients took part and they were split into two groups. Each patient had an equal chance of their treatment starting with either telescopic surgery or shockwave lithotripsy, which was decided by a computer program (via random allocation). We counted how many patients in each group had further procedures to remove their stone. We found that telescopic surgery was 11% more effective overall, with an associated slightly better quality of life (10 more healthy days over the 6-month period), but was more expensive in an NHS setting. The finding of a lack of any significant additional clinical benefit leads to the conclusion that the more cost-effective treatment pathway is shockwave lithotripsy with telescopic surgery used only in those patients in whom shockwave lithotripsy is unsuccessful.

Factors That Influence the Clinical Implementation of Aerobic Exercise in Stroke Rehabilitation: A Theory-Informed Qualitative Study.

OBJECTIVE: Best practice guidelines recommend that aerobic exercise (AEx) be implemented as early as possible poststroke, yet the prescription of AEx remains limited in stroke rehabilitation settings. This study used theoretical frameworks to obtain an in-depth understanding of barriers and enablers to AEx implementation in the stroke rehabilitation setting. METHODS: A qualitative, descriptive study was conducted. Participants were recruited from 4 stroke rehabilitation settings in Ontario, Canada, that have participated in an implementation study to provide structured AEx programming as part of standard care. Six clinician focus groups (with 19 physical therapists and 5 rehabilitation assistants) and one-to-one interviews with 7 managers and 1 physician were conducted to explore barriers and enablers to AEx implementation. The Theoretical Domains Framework and Consolidated Framework for Implementation Research informed content analysis for clinician and manager perspectives, respectively. RESULTS: Barriers specific to resource constraints and health care system pressures, combined with patient goals, led to interventions to improve function being prioritized over AEx. Successful implementation was enabled through an interprofessional approach and team engagement in the planning and implementation process. Health care providers described concerns about patient safety, but confidence and capability for implementing AEx were enabled by education, skill development, use of exercise tests, and consultation with individuals with content expertise. Participants described the development of supportive processes that enabled AEx implementation within team workflows and shared resources. CONCLUSION: Strategies to support implementation of AEx in stroke rehabilitation should incorporate knowledge and skills, the provision of clinical decision-making tools, access to expert consultation, the roles and social influence of the interprofessional team and formal and informal leaders, and supportive processes adapted to the local context. IMPACT: Results from this study will inform the development of a clinical implementation toolkit to support clinical uptake of AEx in the stroke rehabilitation setting.

Assessing potential trade-offs between the lower back and shoulders: influence of lift training intervention on joint demands.

Background. Many of the approaches available for modifying manual materials handling (MMH) exertion emphasize lower back protection but often do not consider how interventions affect other body regions. This study focused on the influence of lift training on resultant joint moments and muscular demand trade-offs between the lower back and shoulders during MMH tasks. Methods. Three recommended lifting techniques (straddle lift, pivot technique and tripod lift) were compared to a priori (untrained) self-selected lifting techniques. Results. Mean and cumulative resultant moments indicated that using the lifting techniques evaluated in this investigation protected the shoulders more than the lower back. Mean and peak shoulder muscle activity also decreased following training (p < 0.05). Although there were no peak and mean changes to lower back muscle activity (p>0.05), there was a significant decrease in cumulative lower back muscle activity (p < 0.05). Reported perceived exertion values decreased following training across the lifting techniques for all evaluated body regions (p < 0.05). Conclusion. Overall, the recommended MMH techniques protected both the lower back and the shoulders, and no exposure trade-offs between them were identified.

The role of theory to develop and evaluate a toolkit to increase clinical measurement and interpretation of walking speed and distance in adults post-stroke.

PURPOSE: The iWalk study showed that 10-meter walk test (10mWT) and 6-minute walk test (6MWT) administration post-stroke increased among physical therapists (PTs) following introduction of a toolkit comprising an educational guide, mobile app, and video. We describe the use of theory guiding toolkit development and a process evaluation. MATERIALS AND METHODS: We used the knowledge-to-action framework to identify research steps; and a guideline implementability framework, self-efficacy theory, and the transtheoretical model to design and evaluate the toolkit and implementation process (three learning sessions). In a before-and-after study, 37 of the 49 participating PTs completed online questionnaires to evaluate engagement with learning sessions, and rate self-efficacy to perform recommended practices pre- and post-intervention. Thirty-three PTs and 7 professional leaders participated in post-intervention focus groups and interviews, respectively. RESULTS: All sites conducted learning sessions; attendance was 50-78%. Self-efficacy ratings for recommended practices increased and were significant for the 10mWT (p ≤ 0.004). Qualitative findings highlighted that theory-based toolkit features and implementation strategies likely facilitated engagement with toolkit components, contributing to observed improvements in PTs' knowledge, attitudes, skill, self-efficacy, and clinical practice. CONCLUSIONS: The approach may help to inform toolkit development to advance other rehabilitation practices of similar complexity.Implications for RehabilitationToolkits are an emerging knowledge translation intervention used to support widespread implementation of clinical practice guideline recommendations.Although experts recommend using theory to inform the development of knowledge translation interventions, there is little guidance on a suitable approach.This study describes an approach to using theories, models and frameworks to design a toolkit and implementation strategy, and a process evaluation of toolkit implementation.Theory-based features of the toolkit and implementation strategy may have facilitated toolkit implementation and practice change to increase clinical measurement and interpretation of walking speed and distance in adults post-stroke.

Use of a Novel EEG-Based Objective Test, the Cognalyzer®, in Quantifying the Strength and Determining the Action Time of Cannabis Psychoactive Effects and Factors that May Influence Them Within an Observational Study Framework.

INTRODUCTION: Current methods to detect recent delta-9-tetrahydrocannabinol (THC) use cannot objectively quantify its psychoactive effects (PE). The Cognalyzer®, an electroencephalography (EEG)-based method, detects and quantifies the strength of THC-induced PE on a scale from 0 to 100%. This study assesses the relationship between the magnitude of Cognalyzer® PE predictions and reported subjective drug effects for 4-h post-cannabis inhalation. METHODS: Seventy-five participants were enrolled in the study. Prior to ad libitum cannabis inhalation, an EEG recording episode was completed. Immediately after inhalation, the Drug Effects Questionnaire (DEQ) was administered and another EEG recording performed. For 25 participants, the study ended. For 50 participants, assessments were repeated at 30-min intervals for 4 h. EEG files were blinded and analyzed using two versions of the Cognalyzer® algorithm. The relationship between the Cognalyzer® PE level results and the DEQ was assessed using generalized linear models and multiple regression. RESULTS: There were significant PE increases from pre-cannabis for up to 3.5 h. Mean reports of feeling drug effects were > 0 at all post-inhalation time points (p ≤ 0.024). Furthermore, there were significant relationships between the Cognalyzer® PE and self-reported perception of drug effects (p ≤ 0.001). Subgroup analysis showed that Cognalyzer® PE levels were impacted by cannabis use history, subjective ratings of drug effects, oral fluid THC concentration and the cannabis product inhaled. CONCLUSION: The findings show that the Cognalyzer® can be used to objectively determine the strength of cannabis psychoactive effects that cannabis products create on consumers and how it changes depending on their experience with cannabis. The Cognalyzer® can be used to conduct scientific consumer research to generate trustworthy informational material about the psychoactive experience of cannabis products. For clinical research, the Cognalyzer® can be used to study the pharmacodynamics of cannabinoids or delivery systems, such as nano-emulsifications.

Level of exoskeleton support influences shoulder elevation, external rotation and forearm pronation during simulated work tasks in females.

Despite growing literature, limited research details the influence of passive upper limb exoskeletons on upper limb kinematics. Two bolting tasks and a tracing task were completed at two heights (overhead and between waist and overhead height) for four exoskeleton conditions (no exoskeleton, and 3 levels of exoskeleton assistance) by female participants. Motion capture data, ratings of perceived exertion and discomfort, and task duration were recorded. Exoskeleton condition increased minimum shoulder elevation by 35-36% (Δ10.5-10.7°) at 1.81 kg and 2.72 kg of support, mean shoulder external rotation by 316% (Δ24.6°) at 0.91 kg of support and mean forearm pronation by 30.9% (Δ14.6°) at 0.91 kg of support. Exoskeleton condition reduced ratings of perceived exertion and discomfort, but not significantly. Task duration was unaffected. Exoskeleton use at any of three different settings modestly affected some joint kinematics for the tasks examined, which may merit consideration when deciding on occupational exoskeleton implementation.

Primary trabeculectomy versus primary glaucoma eye drops for newly diagnosed advanced glaucoma: TAGS RCT.

BACKGROUND: Patients diagnosed with advanced primary open-angle glaucoma are at a high risk of lifetime blindness. Uncertainty exists about whether primary medical management (glaucoma eye drops) or primary surgical treatment (augmented trabeculectomy) provide the best and safest patient outcomes. OBJECTIVES: To compare primary medical management with primary surgical treatment (augmented trabeculectomy) in patients with primary open-angle glaucoma presenting with advanced disease in terms of health-related quality of life, clinical effectiveness, safety and cost-effectiveness. DESIGN: This was a two-arm, parallel, multicentre, pragmatic randomised controlled trial. SETTING: Secondary care eye services. PARTICIPANTS: Adult patients presenting with advanced primary open-angle glaucoma in at least one eye, as defined by the Hodapp-Parrish-Anderson classification of severe glaucoma. INTERVENTION: Primary medical treatment - escalating medical management with glaucoma eye drops. Primary trabeculectomy treatment - trabeculectomy augmented with mitomycin C. MAIN OUTCOME MEASURES: The primary outcome was health-related quality of life measured with the Visual Function Questionnaire-25 at 2 years post randomisation. Secondary outcomes were mean intraocular pressure; EQ-5D-5L; Health Utilities Index 3; Glaucoma Utility Index; cost and cost-effectiveness; generic, vision-specific and disease-specific health-related quality of life; clinical effectiveness; and safety. RESULTS: A total of 453 participants were recruited. The mean age of the participants was 67 years (standard deviation 12 years) in the trabeculectomy arm and 68 years (standard deviation 12 years) in the medical management arm. Over 65% of participants were male and more than 80% were white. At 24 months, the mean difference in Visual Function Questionnaire-25 score was 1.06 (95% confidence interval -1.32 to 3.43; p = 0.383). There was no evidence of a difference between arms in the EQ-5D-5L score, the Health Utilities Index or the Glaucoma Utility Index. At 24 months, the mean intraocular pressure was 12.40 mmHg in the trabeculectomy arm and 15.07 mmHg in the medical management arm (mean difference -2.75 mmHg, 95% confidence interval -3.84 to -1.66 mmHg; p < 0.001). Fewer types of glaucoma eye drops were required in the trabeculectomy arm. LogMAR visual acuity was slightly better in the medical management arm (mean difference 0.07, 95% confidence interval 0.02 to 0.11; p = 0.006) than in the trabeculectomy arm. There was no evidence of difference in safety between the two arms. A discrete choice experiment updated the utility values for the Glaucoma Utility Index. The within-trial economic analysis found a small increase in the mean EQ-5D-5L score (0.04) and that trabeculectomy has a higher probability of being cost-effective than medical management. The incremental cost of trabeculectomy per quality-adjusted life-year was £45,456. Therefore, at 2 years, surgery is unlikely to be considered cost-effective at a threshold of £20,000 per quality-adjusted life-year. When extrapolated over a patient's lifetime in a model-based analysis, trabeculectomy, compared with medical treatment, was associated with higher costs (average £2687), a larger number of quality-adjusted life-years (average 0.28) and higher incremental cost per quality-adjusted life-year gained (average £9679). The likelihood of trabeculectomy being cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life year gained was 73%. CONCLUSIONS: Our results suggested that there was no difference between treatment arms in health-related quality of life, as measured with the Visual Function Questionnaire-25 at 24 months. Intraocular pressure was better controlled in the trabeculectomy arm, and this may reduce visual field progression. Modelling over the patient's lifetime suggests that trabeculectomy may be cost-effective over the range of values of society's willingness to pay for a quality-adjusted life-year. FUTURE WORK: Further follow-up of participants will allow us to estimate the long-term differences of disease progression, patient experience and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56878850. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 72. See the NIHR Journals Library website for further project information.

Glaucoma is an eye condition in which the intraocular pressure is too high, causing damage to the optic nerve and loss of vision. Patients with severe vision loss at diagnosis are the most at risk of blindness in their lifetime. Lowering pressure in the eye is the only way to prevent further vision loss. Two treatments to lower pressure are commonly used: using eye drops or having an operation known as a trabeculectomy. In England, Wales and Northern Ireland, the National Institute for Health and Care Excellence recommends surgery as the first treatment. However, we do not know which treatment is best for preventing vision loss or which is safest, has the best patient experience or provides the best value for money for the NHS. Therefore, surgery is not usually carried out in the first instance and patients start with eye drops instead. This study compared whether starting treatment with eye drops affected the quality of life of patients with advanced glaucoma more or less than starting treatment with trabeculectomy. We also investigated if initial treatment with surgery and initial treatment with eye drops were equally good at controlling pressure and were equally safe, and how much each treatment cost the NHS. Every patient had an equal chance of starting treatment with surgery or eye drops and they participated in the study for 2 years. We found that quality of life was similar regardless of treatment. Those starting with surgery had lower pressure and needed far fewer types of eye drops than those starting with eye drops. Thirty-nine patients in the eye drop arm required surgery to control their glaucoma. Initial treatment with eye drops was cheaper over 2 years' follow-up. Our study suggests that, over a 2-year period, having surgery in the first instance lowers intraocular pressure more than eye drops and is equally as safe as eye drops. Although eye drops are a cheaper treatment option for the NHS, if the effects of surgery on intraocular pressure are lasting, then the increased cost may be justified.

Experiences of Physical Therapists and Professional Leaders With Implementing a Toolkit to Advance Walking Assessment Poststroke: A Realist Evaluation.

OBJECTIVE: The iWalk study showed significant increase in use of the 10-Meter Walk Test (10MWT) and 6-Minute Walk Test (6MWT) poststroke following provision of a toolkit. This paper examined the influence of contextual circumstances on use of the toolkit and implementation strategy across acute care and inpatient and outpatient rehabilitation settings. METHODS: A theory-based toolkit and implementation strategy was designed to support guideline recommendations to use standardized tools for evaluation of walking, education, and goal-setting poststroke. The toolkit comprised a mobile app, video, and educational guide outlining instructions for 3 learning sessions. After completing learning sessions, 33 physical therapists and 7 professional leaders participated in focus groups or interviews. As part of a realist evaluation, the study compared and synthesized site-specific context-mechanism-outcome descriptions across sites to refine an initial theory of how the toolkit would influence practice. RESULTS: Analysis revealed 3 context-mechanism-outcomes: (1) No onsite facilitator? No practice change in acute care: Without an onsite facilitator, participants lacked authority to facilitate and coordinate the implementation strategy; (2) Onsite facilitation fostered integration of select practices in acute care: When onsite facilitation occurred in acute care, walk test administration and use of reference values for patient education were adopted variably with high functioning patients; (3) Onsite facilitation fostered integration of most practices in rehabilitation settings: When onsite facilitation occurred, many participants incorporated 1 or both tests to evaluate and monitor walking capacity, and reference values were applied for inpatient and outpatient education and goal setting. Participants preferentially implemented the 10MWT over the 6MWT because set-up and administration were easier and a greater proportion of patients could walk 10 m. CONCLUSION: Findings underscore contextual factors and activities essential to eliciting change in assessment practice in stroke rehabilitation across care settings. IMPACT: This study shows that to foster recommended walking assessment practices, an onsite facilitator should be present to enable learning sessions and toolkit use.

Electrospun fibre diameter and its effects on vascular smooth muscle cells.

Bypass grafting is a technique used in the treatment of vascular disease, which is currently the leading cause of mortality worldwide. While technology has moved forward over the years, synthetic grafts still show significantly lower rates of patency in small diameter bypass operations compared to the gold standard (autologous vessel grafts). Scaffold morphology plays an important role in vascular smooth muscle cell (VSMC) performance, with studies showing how fibre alignment and surface roughness can modulate phenotypic and genotypic changes. Herein, this study has looked at how the fibre diameter of electrospun polymer scaffolds can affect the performance of seeded VSMCs. Four different scaffolds were electrospun with increasing fibre sizes ranging from 0.75 to 6 µm. Culturing VSMCs on the smallest fibre diameter (0.75 µm) lead to a significant increase in cell viability after 12 days of culture. Furthermore, interesting trends were noted in the expression of two key phenotypic genes associated with mature smooth muscle cell contractility (myocardin and smooth muscle alpha-actin 1), whereby reducing the fibre diameter lead to relative upregulations compared to the larger fibre diameters. These results showed that the smallest (0.75 µm) fibre diameter may be best suited for the culture of VSMCs with the aim of increasing cell proliferation and aiding cell maturity.

A Randomized, Triple-Blind, Placebo-Controlled, Crossover Study to Investigate the Efficacy of a Single Dose of AlphaWave® L-Theanine on Stress in a Healthy Adult Population.

INTRODUCTION: Stress is a complex life occurrence essential for survival and goal achievement but can be damaging in excess. Because of the high prevalence of stress in North America, a safe supplement that effectively reduces stress is in demand. The objective of this study was to investigate the efficacy and safety of AlphaWave® L-Theanine on whole-scalp and frontal alpha power, midline theta power, and salivary cortisol in healthy, moderately stressed adults. METHODS: This was a randomized, triple-blind, placebo-controlled, crossover study that consisted of two study periods with a 7-day washout. A single dose of AlphaWave® L-Theanine (200 mg) or placebo was administered. To induce stress, a mental arithmetic test (MAT) was administered before and after the dose. Electroencephalogram, salivary cortisol, blood pressure, heart rate, self-reported stress, adverse events, clinical chemistry, and hematology were assessed to evaluate efficacy and safety. RESULTS: Increases in heart rate, blood pressure, and self-reported stress and state anxiety indicated that participants experienced stress during the MAT. AlphaWave® L-Theanine led to a greater increase in frontal region and whole-scalp alpha power 3 h post-dose compared to placebo (p ≤ 0.050). Within groups, there were increases in alpha power, at 3 h with AlphaWave® L-Theanine, over the whole recording and during the eyes-open portions (p ≤ 0.048) of the alpha task. The changes in alpha wave activity are supported by greater decreases in salivary cortisol 1 h post-dose (p < 0.001) with AlphaWave® L-Theanine compared to placebo. CONCLUSION: This study was conducted during the SARS-CoV-2 pandemic, which has had a rapid and significant effect on both physical and mental health around the world. A single dose of AlphaWave® L-Theanine significantly increased frontal region alpha power compared to placebo in response to an acute stress challenge. These changes are indicative of relaxation in the brain and suggest a calming response. AlphaWave® L-Theanine was found to be safe and well tolerated by participants. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04706494.

Stress is a complex part of life that is essential for survival and achieving goals. Too much stress, however, can be damaging. There is a high prevalence of stress in North America, creating a demand for a safe and effective supplement to reduce it. This study investigated the effectiveness and safety of AlphaWave^® L-Theanine on brainwaves and salivary cortisol in healthy, moderately stressed adults facing an acute stressor. This was a randomized, triple-blind, placebo-controlled, crossover study that consisted of two study periods with a 7-day washout. A single dose of 200 mg of AlphaWave^® L-Theanine or placebo was administered before and after a mental arithmetic test to elicit acute stress. Electroencephalogram, salivary cortisol, blood pressure, heart rate, self-reported stress, and safety were assessed to evaluate efficacy and safety. This study was conducted during the coronavirus pandemic, which has had a rapid and significant effect on both physical and mental health around the world. A single dose of AlphaWave^® L-Theanine had significant positive effects on brainwaves, salivary cortisol, and self-reported state anxiety compared to the placebo in response to an acute stress challenge. These changes are indicative of relaxation in the brain and suggest a calming response in a moderately stressed but otherwise healthy population. AlphaWave^® L-Theanine was found to be safe and well tolerated by participants.

Advanced preclinical models for evaluation of drug-induced liver injury - consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET].

Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception: the Bridge-it RCT.

INTRODUCTION: Unless women start effective contraception after using emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies that are unable to provide ongoing contraception (apart from barrier methods which have high failure rates). This means that women need an appointment with a general practitioner or at a sexual and reproductive health clinic. We conducted a pragmatic cluster randomised cohort crossover trial to determine whether or not pharmacist provision of a bridging supply of a progestogen-only pill plus the invitation to attend a sexual and reproductive health clinic resulted in increased subsequent use of effective contraception (hormonal or intrauterine). METHODS: Twenty-nine pharmacies in three UK cities recruited women receiving emergency contraception (levonorgestrel). In the intervention, women received a 3-month supply of the progestogen-only pill (75 µg of desogestrel) plus a card that provided rapid access to a local sexual and reproductive health clinic. In the control arm, pharmacists advised women to attend their usual contraceptive provider. The primary outcome was reported use of an effective contraception (hormonal and intrauterine methods) at 4 months. Process evaluation was also conducted to inform any future implementation. RESULTS: The study took place December 2017 and June 2019 and recruited 636 women to the intervention (n = 316) and control groups (n = 320). There were no statistically significant differences in demographic characteristics between the groups. Four-month follow-up data were available for 406 participants: 63% (198/315) of the control group and 65% (208/318) of the intervention group. The proportion of participants reporting use of effective contraception was 20.1% greater (95% confidence interval 5.2% to 35.0%) in the intervention group (58.4%, 95% confidence interval 48.6% to 68.2%) than in the control group (40.5%, 95% confidence interval 29.7% to 51.3%) (adjusted for recruitment period, treatment arm and centre; p = 0.011). The proportion of women using effective contraception remained statistically significantly larger, when adjusted for age, current sexual relationship and history of past use of effective contraception, and was robust to the missing data. There were no serious adverse events. CONCLUSION: Provision of a bridging supply of the progestogen-only pill with emergency contraception from a pharmacist and the invitation to a sexual and reproductive health clinic resulted in a significant increase in self-reported subsequent use of effective contraception. This simple intervention has the potential to prevent more unintended pregnancies for women after emergency contraception. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70616901. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 27. See the NIHR Journals Library website for further project information.

The emergency contraceptive pill can prevent pregnancy following unprotected sex or a burst condom; however, unless women start a regular method of contraception they remain at risk of pregnancy. Most women obtain emergency contraception from a community pharmacy (chemist), but then require an appointment with a general practitioner or at a sexual and reproductive health clinic for ongoing contraception. Getting an appointment can take time and unintended pregnancies can occur during this time. If a pharmacist could give women a small supply of a progestogen-only pill or 'mini-pill' with their emergency contraception, together with help to get an appointment at a clinic, then this might help more women to start effective contraception. We undertook a study in 29 pharmacies in Lothian, Tayside and London among women receiving emergency contraception. Pharmacists provided either their standard advice about contraception (control group) or the intervention. The intervention was a 3-month supply of the progestogen-only pill plus a rapid-access card, which, if presented at a sexual and reproductive health clinic, would help women get an appointment for contraception. The order in which the pharmacy provided either control or intervention was randomised. We conducted telephone interviews with the women 4 months later to find out what contraception they were using. A total of 636 women took part in the study, 316 in the intervention group and 320 in the control group. The proportion who said that they were using an effective method of contraception was around 20% larger in the intervention group. In addition, fewer women in this group said that they had used emergency contraception again. This study shows that community pharmacy provision of a small supply of progestogen-only pills and the invitation to attend a sexual and reproductive health clinic results in a large increase in the use of effective contraception after emergency contraception. If this became routine practice then it could help prevent unintended pregnancies.

Higher body mass index and body fat percentage correlate to lower joint and functional strength in working age adults.

As the prevalence of obesity grows worldwide, it becomes an increasing concern in working populations. Ergonomists are faced with the challenge of accommodating workplace layouts to include this worker demographic. This study investigated the relationship between shoulder and low back isometric joint strengths across body mass index (BMI) groups. Additionally, relationships between body fat percentage (BF%), absolute strength, and strength normalized to body mass were examined. Ninety, healthy, working age participants performed 11 functional and isometric joint strength exertions. BMI group influenced normalized strength, as the obese 2+ (BMI >35.0) group had up to 63.1% lower joint strength than all other BMI groups (p < 0.05). Significant strong to moderate negative linear relationships existed between BF% and normalized strength for both males and females, and relationships were stronger for females. These strength deficits highlight the importance of considering body composition during ergonomics analyses and configuration of occupational tasks.

Primary trabeculectomy for advanced glaucoma: pragmatic multicentre randomised controlled trial (TAGS).

OBJECTIVE: To determine whether primary trabeculectomy or primary medical treatment produces better outcomes in term of quality of life, clinical effectiveness, and safety in patients presenting with advanced glaucoma. DESIGN: Pragmatic multicentre randomised controlled trial. SETTING: 27 secondary care glaucoma departments in the UK. PARTICIPANTS: 453 adults presenting with newly diagnosed advanced open angle glaucoma in at least one eye (Hodapp classification) between 3 June 2014 and 31 May 2017. INTERVENTIONS: Mitomycin C augmented trabeculectomy (n=227) and escalating medical management with intraocular pressure reducing drops (n=226) MAIN OUTCOME MEASURES: Primary outcome: vision specific quality of life measured with Visual Function Questionnaire-25 (VFQ-25) at 24 months. SECONDARY OUTCOMES: general health status, glaucoma related quality of life, clinical effectiveness (intraocular pressure, visual field, visual acuity), and safety. RESULTS: At 24 months, the mean VFQ-25 scores in the trabeculectomy and medical arms were 85.4 (SD 13.8) and 84.5 (16.3), respectively (mean difference 1.06, 95% confidence interval -1.32 to 3.43; P=0.38). Mean intraocular pressure was 12.4 (SD 4.7) mm Hg for trabeculectomy and 15.1 (4.8) mm Hg for medical management (mean difference -2.8 (-3.8 to -1.7) mm Hg; P<0.001). Adverse events occurred in 88 (39%) patients in the trabeculectomy arm and 100 (44%) in the medical management arm (relative risk 0.88, 95% confidence interval 0.66 to 1.17; P=0.37). Serious side effects were rare. CONCLUSION: Primary trabeculectomy had similar quality of life and safety outcomes and achieved a lower intraocular pressure compared with primary medication. TRIAL REGISTRATION: Health Technology Assessment (NIHR-HTA) Programme (project number: 12/35/38). ISRCTN registry: ISRCTN56878850.