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Abstract Adverse events suffer from poor reporting within randomised controlled trials, despite them being crucial to the evaluation of a treatment. A recent update to the CONSORT harms checklist aims to improve reporting by providing structure and consistency to the information presented. We propose an extension wherein harms would be reported in conjunction with effectiveness outcome(s) rather than in silo to provide a more complete picture of the evidence acquired within a trial. Benefit-risk methods are designed to simultaneously consider both benefits and risks, and therefore, we believe these methods could be implemented to improve the prominence of adverse events when reporting trials. The aim of this article is to use case studies to demonstrate the practical utility of benefit-risk methods to present adverse events results alongside effectiveness results. Two randomised controlled trials have been selected as case studies, the Option-DM trial and the SANAD II trial. Using a previous review, a shortlist of 17 benefit-risk methods which could potentially be used for reporting RCTs was created. From this shortlist, three benefit-risk methods are applied across the two case studies. We selected these methods for their usefulness to achieve the aim of this paper and which are commonly used in the literature. The methods selected were the Benefit-Risk Action Team (BRAT) Framework, net clinical benefit (NCB), and the Outcome Measures in Rheumatology (OMERACT) 3 × 3 table. Results using the benefit-risk method added further context and detail to the clinical summaries made from the trials. In the case of the SANAD II trial, the clinicians concluded that despite the primary outcome being improved by the treatment, the increase in adverse events negated the improvement and the treatment was therefore not recommended. The benefit-risk methods applied to this case study outlined the data that this decision was based on in a clear and transparent way. Using benefit-risk methods to report the results of trials can increase the prominence of adverse event results by presenting them alongside the primary efficacy/effectiveness outcomes. This ensures that all the factors which would be used to determine whether a treatment would be recommended are transparent to the reader.

Commentary: Were they being properly reported, two critically important court hearings in February 2024, in London and The Hague, would expose the US ‘rules-based order’ as a hollow sham. Both posed globe-spanning threats to our most basic freedoms. Neither received more than perfunctory coverage in Western establishment media such as the BBC. One was a week-long hearing by the International Court of Justice (ICJ) over a United Nations General Assembly request for an advisory opinion over Israel’s illegal occupation of the Palestinian territories and the other was a last-ditch appeal of WikiLeaks founder Julian Assange against efforts by the United States to extradite him so that he can be locked away for the rest of his life. EDITORIAL NOTE: After the editorial of Pacific Journalism Review and the lead article in this edition (Vol 30, No 1&2) about the fate of WikiLeaks founder Julian Assange were printed, the Australian journalist was set free and he arrived back in Australia after a plea bargain. The winner of his country’s Walkley Award for journalism excellence, Assange was freed by a US federal court in Saipan, Northern Mariana Islands, on 26 June 2024 after a plea bargain to plead guilty to one charge of violating the US Espionage Act and the judge sentenced him to 62 months, jail time already served in the UK on remand. His 14-year struggle for freedom was over, but his lawyers say they will press for a full US presidential pardon.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Rapid growth in the number of small sensor devices known as the Internet of Things (IoT) has seen the development of lightweight encryption algorithms. Two well-known lightweight algorithms are SIMON and SIMECK which have been specifically designed for use on resource-constrained IoT devices. These lightweight encryption algorithms are based on the efficient Feistel block structure which is known to exhibit vulnerabilities to differential cryptanalysis. Consequently, it is necessary to test these algorithms for resilience against such attacks. While existing state-of-the-art research has demonstrated novel heuristic methods of differential cryptanalysis that improve time efficiency on previous techniques, the large state sizes of these encryption algorithms inhibit cryptanalysis time efficiency. In this paper, we introduce Versatile Investigative Sampling Technique for Advanced Cryptanalysis (VISTA-CRYPT) - a time-efficient enhancement of differential cryptanalysis of lightweight encryption algorithms. The proposed technique introduces a simple framework of quota sampling that produces state-of-the-art results with time reductions of up to 76% over existing techniques. Further, we present a preliminary graph-based analysis of the output differentials for the identification of relationships within the data and future research opportunities to further enhance the performance of differential cryptanalysis. The code designed for this work and associated datasets is available at https://github.com/johncook1979/simon-cryptanalysis.

Abstract Background Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone. Methods This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results). Discussion We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care. Trial registration IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).

Aims: Symptomatic spinal stenosis is a very common problem, and decompression surgery has been shown to be superior to nonoperative treatment in selected patient groups. However, performing an instrumented fusion in addition to decompression may avoid revision and improve outcomes. The aim of the SpInOuT feasibility study was to establish whether a definitive randomized controlled trial (RCT) that accounted for the spectrum of pathology contributing to spinal stenosis, including pelvic incidence-lumbar lordosis (PI-LL) mismatch and mobile spondylolisthesis, could be conducted. Methods: As part of the SpInOuT-F study, a pilot randomized trial was carried out across five NHS hospitals. Patients were randomized to either spinal decompression alone or spinal decompression plus instrumented fusion. Patient-reported outcome measures were collected at baseline and three months. The intended sample size was 60 patients. Results: Of the 90 patients screened, 77 passed the initial screening criteria. A total of 27 patients had a PI-LL mismatch and 23 had a dynamic spondylolisthesis. Following secondary inclusion and exclusion criteria, 31 patients were eligible for the study. Six patients were randomized and one underwent surgery during the study period. Given the low number of patients recruited and randomized, it was not possible to assess completion rates, quality of life, imaging, or health economic outcomes as intended. Conclusion: This study provides a unique insight into the prevalence of dynamic spondylolisthesis and PI-LL mismatch in patients with symptomatic spinal stenosis, and demonstrates that there is a need for a definitive RCT which stratifies for these groups in order to inform surgical decision-making. Nonetheless a definitive study would need further refinement in design and implementation in order to be feasible. Cite this article: Bone Jt Open 2023;4(8):573–579.

The growth in the use of small sensor devices, commonly known as the Internet of Things (IoT), has resulted in unprecedented amounts of data being generated and captured. With the rapidly growing popularity of personal IoT devices, the collection of personal data through such devices has also increased exponentially. To accommodate the anticipated growth in connected devices, researchers are now investigating futuristic network technologies that are capable of processing large volumes of information at much faster speeds. However, the introduction of innovative network technologies coupled with existing vulnerabilities of personal IoT devices and insufficient device security standards is resulting in new challenges for the security of data collected on these devices. While existing research has focused on the technical aspects of security vulnerabilities and solutions in either network or IoT technologies separately, this paper thoroughly investigates common aspects impacting IoT security on existing and futuristic networks, including human-centric issues and the mechanisms that can lead to loss of confidentiality. By undertaking a comprehensive literature review of existing research, this article has identified five key areas that impact IoT security for futuristic next generation networks. Furthermore, by extensively analysing each area, the article reports on conclusive findings and future research opportunities for IoT privacy and security for the next generation of network technologies.

BackgroundJournal articles describing randomized controlled trials (RCTs) and systematic reviews with meta-analysis of RCTs are not optimally reported and often miss crucial details. This poor reporting makes assessing these studies’ risk of bias or reproducing their results difficult. However, the reporting quality of diet- and nutrition-related RCTs and meta-analyses has not been explored. ObjectiveWe aimed to assess the reporting completeness and identify the main reporting limitations of diet- and nutrition-related RCTs and meta-analyses of RCTs, estimate the frequency of reproducible research practices among these RCTs, and estimate the frequency of distorted presentation or spin among these meta-analyses. MethodsTwo independent meta-research studies will be conducted using articles published in PubMed-indexed journals. The first will include a sample of diet- and nutrition-related RCTs; the second will include a sample of systematic reviews with meta-analysis of diet- and nutrition-related RCTs. A validated search strategy will be used to identify RCTs of nutritional interventions and an adapted strategy to identify meta-analyses in PubMed. We will search for RCTs and meta-analyses indexed in 1 calendar year and randomly select 100 RCTs (June 2021 to June 2022) and 100 meta-analyses (July 2021 to July 2022). Two reviewers will independently screen the titles and abstracts of records yielded by the searches, then read the full texts to confirm their eligibility. The general features of these published RCTs and meta-analyses will be extracted into a research electronic data capture database (REDCap; Vanderbilt University). The completeness of reporting of each RCT will be assessed using the items in the CONSORT (Consolidated Standards of Reporting Trials), its extensions, and the TIDieR (Template for Intervention Description and Replication) statements. Information about practices that promote research transparency and reproducibility, such as the publication of protocols and statistical analysis plans will be collected. There will be an assessment of the completeness of reporting of each meta-analysis using the items in the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and collection of information about spin in the abstracts and full-texts. The results will be presented as descriptive statistics in diagrams or tables. These 2 meta-research studies are registered in the Open Science Framework. ResultsThe literature search for the first meta-research retrieved 20,030 records and 2182 were potentially eligible. The literature search for the second meta-research retrieved 10,918 records and 850 were potentially eligible. Among them, random samples of 100 RCTs and 100 meta-analyses were selected for data extraction. Data extraction is currently in progress, and completion is expected by the beginning of 2023. ConclusionsOur meta-research studies will summarize the main limitation on reporting completeness of nutrition- or diet-related RCTs and meta-analyses and provide comprehensive information regarding the particularities in the reporting of intervention studies in the nutrition field. International Registered Report Identifier (IRRID)DERR1-10.2196/43537

Introduction Surgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS).Methods and analysis This is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial comparing the addition of DTI and iUS to the standard of care surgery. A total of 357 patients will be recruited for the RCT. The primary outcome is DFS, defined as the time to either 10-point deterioration in health-related quality of life scores from baseline, without subsequent reversal, progressive disease or death.Ethics and dissemination The trial was registered in the Integrated Research Application System (Ref: 264482) and approved by a UK research and ethics committee (Ref: 20/LO/0840). Results will be published in a peer-reviewed journal. Further dissemination to participants, patient groups and the wider medical community will use a range of approaches to maximise impact.Trial registration number ISRCTN38834571.

Abstract Background Segmental tibial fractures are fractures in two or more areas of the tibial diaphysis resulting in a separate intercalary segment of the bone. Surgical fixation is recommended for patients with segmental tibial fractures as non-operative treatment outcomes are poor. The most common surgical interventions are intramedullary nailing (IMN) and circular frame external fixation (CFEF), but evidence about which is better is of poor quality. An adequately powered randomised controlled trial (RCT) to determine optimum treatment is required. STIFF-F aimed to assess the feasibility of a multicentre RCT comparing IMN with CFEF for segmental tibial fracture. Methods STIFF-F was a mixed-methods feasibility study comprising a pilot RCT conducted at six UK Major Trauma Centres, qualitative interviews drawing on Phenomenology and an online survey of rehabilitation. The primary outcome was recruitment rate. Patients, 16 years and over, with a segmental tibial fracture (open or closed) deemed suitable for IMN or CFEF were eligible to participate. Randomisation was stratified by site using random permuted blocks of varying sizes. Participant or assessor blinding was not possible. Interviews were undertaken with patients about their experience of injury, treatment, recovery and participation. Staff were interviewed to identify contextual factors affecting trial processes, their experience of recruitment and the treatment pathway. An online survey was developed to understand the rehabilitation context of the treatments. Results Eleven patients were screened and three recruited to the pilot RCT. Nineteen staff and four patients participated in interviews, and 11 physiotherapists responded to the survey. This study found the following: (i) segmental tibial fractures were rarer than anticipated, (ii) the complexity of the injury, study setup times and surgeon treatment preferences impeded recruitment, (iii) recovery from a segmental tibial fracture is challenging, and rehabilitation protocols are inconsistent and (iv) despite the difficulty recruiting, staff valued this research question and strived to find a way forward. Conclusion The proposed multicentre RCT comparing IMN with CFEF is not feasible. This study highlighted the difficulty of recruiting patients to an RCT of a complex rare injury over a short time period. Trial registration The study was registered with the International Standard Randomised Controlled Trials Number Registry: ISRCTN11229660

Abstract Background Depending on the treatment to be investigated, a clinical trial could be designed to assess objectives of superiority, equivalence or non-inferiority. The design of the study is affected by many different elements including the control treatment, the primary outcome and associated relationships. In some studies, there could be more than one outcome of interest. In these situations, benefit-risk methodologies could be used to assess the outcomes simultaneously and consider the trade-off between the benefits against the risks of a treatment. Benefit-risk is used within the regulatory industry but seldom included within publicly funded clinical trials within the UK. This project aims to gain an expert consensus on how to select the appropriate trial design (e.g. superiority) and when to consider including benefit-risk methods. Methods The project will consist of four work packages: 1. A web-based survey to elicit current experiences and opinions, 2. A rapid literature review to assess any current recommendations, 3. A two-day consensus workshop to gain agreement on the recommendations, and 4. Production of a guidance document. Discussion The aim of the project is to provide a guideline for clinical researchers, grant funding bodies and reviewers for grant bodies for how to select the most appropriate trial design and when it is appropriate to consider using benefit-risk methods. The focus of the guideline will be on publicly funded trials however, the vision is that the work will be applicable across research settings and we will connect with other organisations and committees as appropriate.

Abstract Background Anterior cruciate ligament (ACL) rupture is a common knee injury that can lead to poor quality of life, decreased activity and increased risk of secondary osteoarthritis of the knee. Management of patients with a non-acute ACL injury can include a non-surgical (rehabilitation) or surgical (reconstruction) approach. However, insufficient evidence to guide treatment selection has led to high variation in treatment choice for patients with non-acute presentation of ACL injury. The objective of the ACL SNNAP trial is to determine in patients with non-acute anterior cruciate ligament deficiency (ACLD) whether a strategy of non-surgical management (rehabilitation) (with option for later ACL reconstruction only if required) is more clinically effective and cost effective than a strategy of surgical management (reconstruction) without prior rehabilitation with all patients followed up at 18 months. Methods The study is a pragmatic, multi-centre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Patients with a symptomatic non-acute ACL deficient knee will be randomised to either non-surgical management (rehabilitation) or surgical management (reconstruction). We aim to recruit 320 patients from approximately 30 secondary care orthopaedic units from across the United Kingdom. Randomisation will occur using a web-based randomisation system. Blinding of patients and clinicians to treatment allocation will not be possible because of the nature of the interventions. Participants will be followed up via self-reported questionnaires at 6, 12 and 18 months. The primary outcome is the Knee injury and Osteoarthritis Outcome Score (KOOS) at 18 months post randomisation. Secondary outcomes will include a return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee specific quality of life and resource usage. Discussion At present, no evidence-based treatment of non-acute ACL deficiency exists, particularly in the NHS. Moreover, little consensus exists on the management approach for these patients. The proposed trial will address this gap in knowledge regarding the clinical and cost effectiveness of ACL treatment and inform future standards of care for this condition. Trial registration ISRCTN: 10110685 . Registered on 16 November 2016. ClinicalTrials.gov: NCT02980367 . Registered in December 2016.

Background: Patients with a displaced fracture of the distal radius are frequently offered surgical fixation. Manipulation of the fracture and moulded plaster casting is an alternative treatment that avoids metal implants, but evidence of its effectiveness is lacking. Objective: To compare functional outcomes, quality-of-life outcomes, complications and resource use among patients with a dorsally displaced fracture of the distal radius treated with manipulation and surgical fixation with Kirschner wires (K-wires) and those treated with manipulation and moulded cast. Design: Pragmatic, superiority, multicentre, randomised controlled trial with a health economic evaluation. Setting: A total of 36 orthopaedic trauma centres in the UK NHS. Participants: Patients (aged ≥ 16 years) treated for an acute dorsally displaced fracture of the distal radius were potentially eligible. Patients were excluded if their injury had occurred > 2 weeks previously, if the fracture was open, if it extended > 3 cm from the radiocarpal joint or if it required open reduction, or if the participant was unable to complete questionnaires. Interventions: Participants were randomly assigned in theatre (1 : 1) to receive a moulded cast (i.e. the cast group) or surgical fixation with K-wires (i.e. the K-wire group) after fracture manipulation. Main outcome measures: The primary outcome measure was the Patient-Rated Wrist Evaluation score at 12 months, analysed on an intention-to-treat basis. Health-related quality of life was recorded using the EuroQol-5 Dimensions, five-level version, and resource use was recorded from a health and personal social care perspective. Results: Between January 2017 and March 2019, 500 participants (mean age 60 years, 83% women) were randomly allocated to receive a moulded cast (n = 255) or surgical fixation with K-wire (n = 245) following a manipulation of their fracture. A total of 395 (80%) participants were included in the primary analysis at 12 months. There was no difference in the Patient-Rated Wrist Evaluation score at 1 year post randomisation [cast group: n = 200, mean score 21.2 (standard deviation 23.1); K-wire group: n = 195, mean score 20.7 (standard deviation 22.3); adjusted mean difference –0.34 (95% confidence interval –4.33 to 3.66); p = 0.87]. A total of 33 (13%) participants in the cast group required surgical fixation for loss of fracture position in the first 6 weeks, compared with one participant in the K-wire group (odds ratio 0.02, 95% confidence interval 0.001 to 0.10). The base-case cost-effectiveness analysis showed that manipulation and surgical fixation with K-wires had a higher mean cost than manipulation and a moulded cast, despite similar mean effectiveness. The use of K-wires is unlikely to be cost-effective, and sensitivity analyses found this result to be robust. Limitations: Because the interventions were identifiable, neither patients nor clinicians could be blind to their treatment. Conclusions: Surgical fixation with K-wires was not found to be superior to moulded casting following manipulation of a dorsally displaced fracture of the distal radius, as measured by Patient-Rated Wrist Evaluation score. However, one in eight participants treated in a moulded cast required surgery for loss of fracture reduction in the first 6 weeks. After a successful closed reduction, clinicians may consider a moulded cast as a safe and cost-effective alternative to surgical fixation with K-wires. Future work: Further research should focus on optimal techniques for immobilisation and manipulation of this type of fracture, including optimal analgesia, and for rehabilitation of the patient after immobilisation. Trial registration: This trial is registered as ISRCTN11980540 and UKCRN Portfolio 208830. 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. 11. See the NIHR Journals Library website for further project information.

Abstract Background Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. Methods SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0–10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. Discussion The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. Trial registration ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017.

AbstractSuction-assisted lipectomy (or “liposuction”) is a fundamental technique for all plastic surgeons, and like many procedures in aesthetic surgery, its applications are continuing to evolve. With the rapid introduction of new technologies, many plastic surgeons are left with questions about how these new devices work, what results to expect, and how to best apply these technologies in their practice. We recognized that there is a need for unbiased recommendations to guide surgeons on how to approach current liposuction devices (as well as their adjuncts) and how to use them effectively for their patients. Using available literature and personal experience, we answer the most common questions that we hear from our plastic surgery colleagues.

Background The global burden of disease in children is large and disproportionally affects low-income and middle-income countries (LMICs). Geospatial analysis offers powerful tools to quantify and visualise disparities in surgical care in LMICs. Our study aims to analyse the geographical distribution of paediatric surgical conditions and to evaluate the geographical access to surgical care in Somaliland.Methods Using the Surgeons OverSeas Assessment of Surgical Need survey and a combined survey from the WHO’s (WHO) Surgical Assessment Tool—Hospital Walkthrough and the Global Initiative for Children’s Surgery Global Assessment in Paediatric Surgery, we collected data on surgical burden and access from 1503 children and 15 hospitals across Somaliland. We used several geospatial tools, including hotspot analysis, service area analysis, Voronoi diagrams, and Inverse Distance Weighted interpolation to estimate the geographical distribution of paediatric surgical conditions and access to care across Somaliland.Results Our analysis suggests less than 10% of children have timely access to care across Somaliland. Patients could travel up to 12 hours by public transportation and more than 2 days by foot to reach surgical care. There are wide geographical disparities in the prevalence of paediatric surgical conditions and access to surgical care across regions. Disparities are greater among children travelling by foot and living in rural areas, where the delay to receive surgery often exceeds 3 years. Overall, Sahil and Sool were the regions that combined the highest need and the poorest surgical care coverage.Conclusion Our study demonstrated wide disparities in the distribution of surgical disease and access to surgical care for children across Somaliland. Geospatial analysis offers powerful tools to identify critical areas and strategically allocate resources and interventions to efficiently scale-up surgical care for children in Somaliland.

Abstract Background MACRO (Defining best Management for Adults with Chronic RhinOsinusitis) is an NIHR-funded programme of work designed to establish best practice for adults with chronic rhinosinusitis (CRS). The 7-year programme comprises three consecutive workstreams, designed to explore NHS care pathways through analysis of primary and secondary data sources, and to undertake a randomised controlled trial to evaluate a longer-term course of macrolide antibiotics and endoscopic sinus surgery for patients with CRS. A number of outstanding elements still required clarification at the funding stage. This paper reports an expert panel review process designed to agree and finalise the MACRO trial design, ensuring relevance to patients and clinicians whilst maximising trial recruitment and retention. Methods An expert panel, consisting of the MACRO Programme Management Group, independent advisors, and patient contributors, was convened to review current evidence and the mixed-method data collected as part of the programme, and reach agreement on MACRO trial design. Specifically, agreement was sought for selection of macrolide antibiotic, use of orally administered steroids, inclusion of CRS phenotypes (with/without nasal polyps), and overall trial design. Results A 12-week course of clarithromycin was agreed as the main trial comparator due to its increasing use as a first- and second-line treatment for patients with CRS, and the perceived need to establish its role in CRS management. Orally administered steroids will be used as a rescue medication during the trial, rather than routinely either pre or post trial randomisation, to limit any potential effects on surgical outcomes and better reflect current UK prescribing habits. Both CRS phenotypes will be included in a single trial to ensure that the MACRO trial is both pragmatic and generalisable to primary care. A modified, three-arm trial design was agreed after intense discussions and further exploratory work. Inclusion criteria were amended to ensure that the patients recruited would be considered eligible for the treatment offered in the trial due to having already received appropriate medical therapy as deemed suitable by their ENT surgeon. A proposed 6-week run-in period prior to randomisation was removed due to the new criteria prior to randomisation. Conclusion The expert panel review process resulted in agreement on key elements and an optimal design for the MACRO trial, considered most likely to be successful in terms of both recruitment potential and ability to establish best management of patients with CRS.

Abstract Background Chronic rhinosinusitis (CRS) is a common source of ill health; 11% of UK adults reported CRS symptoms in a worldwide population study. Guidelines are conflicting regarding whether antibiotics should be included in primary medical management, reflecting the lack of evidence in systematic reviews. Insufficient evidence to inform the role of surgery contributes to a fivefold variation in UK intervention rates. The objective of this trial is to establish the comparative effectiveness of endoscopic sinus surgery (ESS) or a prolonged course of antibiotics (clarithromycin) in adult patients with CRS in terms of symptomatic improvement and costs to the National Health Service compared with standard medical care (intranasal medication) at 6 months. Methods/design A three-arm parallel-group trial will be conducted with patients who remain symptomatic after receiving appropriate medical therapy (either in primary or secondary care). They will be randomised to receive: (1) intranasal medication plus ESS, (2) intranasal medication plus clarithromycin (250 mg) or (3) intranasal medication plus a placebo. Intranasal medication (current standard medical care) is defined as a spray or drops of intranasal corticosteroids and saline irrigations. The primary outcome measure is the SNOT-22 questionnaire, which assesses disease-specific health-related quality of life. The study sample size is 600. Principal analyses will be according to the randomised groups irrespective of compliance. The trial will be conducted in at least 16 secondary or tertiary care centres with an internal pilot at six sites for 6 months. Discussion The potential cardiovascular side effects of macrolide antibiotics have been recently highlighted. The effectiveness of antibiotics will be established through this trial, which may help to reduce unnecessary usage and potential morbidity. If ESS is shown to be clinically effective and cost-effective, the trial may encourage earlier intervention. In contrast, if it is shown to be ineffective, then there should be a significant reduction in surgery rates. The trial results will feed into the other components of the MACRO research programme to establish best practice for the management of adults with CRS and design the ideal patient pathway across primary and secondary care. Trial registration ISRCTN36962030. Registered on 17 October 2018.

Background: Owing to the increasing prevalence of diabetes, the workload related to diabetic macular oedema and proliferative diabetic retinopathy is rising, making it difficult for hospital eye services to meet demands. Objective: The objective was to evaluate the diagnostic performance, cost-effectiveness and acceptability of a new pathway using multimodal imaging interpreted by ophthalmic graders to detect reactivation of diabetic macular oedema/proliferative diabetic retinopathy in previously treated patients. Design: This was a prospective, case-referent, cross-sectional diagnostic study. Setting: The setting was ophthalmic clinics in 13 NHS hospitals. Participants: Adults with type 1 or type 2 diabetes with previously successfully treated diabetic macular oedema/proliferative diabetic retinopathy in one/both eyes in whom, at the time of enrolment, diabetic macular oedema/proliferative diabetic retinopathy could be active or inactive. Methods: For the ophthalmic grader pathway, review of the spectral domain optical coherence tomography scans to detect diabetic macular oedema, and seven-field Early Treatment Diabetic Retinopathy Study/ultra-wide field fundus images to detect proliferative diabetic retinopathy, by trained ophthalmic graders. For the current standard care pathway (reference standard), ophthalmologists examined patients face to face by slit-lamp biomicroscopy for proliferative diabetic retinopathy and, in addition, spectral domain optical coherence tomography imaging for diabetic macular oedema. Outcome measures: The primary outcome measure was sensitivity of the ophthalmic grader pathway to detect active diabetic macular oedema/proliferative diabetic retinopathy. The secondary outcomes were specificity, agreement between pathways, cost–consequences, acceptability and the proportion of patients requiring subsequent ophthalmologist assessment, unable to undergo imaging and with inadequate quality images/indeterminate findings. It was assumed for the main analysis that all patients in whom graders diagnosed active disease or were ‘unsure’ or images were ‘ungradable’ required examination by an ophthalmologist. Results: Eligible participants with active and inactive diabetic macular oedema (152 and 120 participants, respectively) and active and inactive proliferative diabetic retinopathy (111 and 170 participants, respectively) were recruited. Under the main analysis, graders had a sensitivity of 97% (142/147) (95% confidence interval 92% to 99%) and specificity of 31% (35/113) (95% confidence interval 23% to 40%) to detect diabetic macular oedema. For proliferative diabetic retinopathy, graders had a similar sensitivity and specificity using seven-field Early Treatment Diabetic Retinopathy Study [sensitivity 85% (87/102), 95% confidence interval 77% to 91%; specificity 48% (77/160), 95% confidence interval 41% to 56%] or ultra-wide field imaging [sensitivity 83% (87/105), 95% confidence interval 75% to 89%; specificity 54% (86/160), 95% confidence interval 46% to 61%]. Participants attending focus groups expressed preference for face-to-face evaluations by ophthalmologists. In the ophthalmologists’ absence, patients voiced the need for immediate feedback following grader’s assessments, maintaining periodic evaluations by ophthalmologists. Graders and ophthalmologists were supportive of the new pathway. When compared with the reference standard (current standard pathway), the new grader pathway could save £1390 per 100 patients in the review of people with diabetic macular oedema and, depending on the imaging modality used, between £461 and £1189 per 100 patients in the review of people with proliferative diabetic retinopathy. Conclusions: For people with diabetic macular oedema, the ophthalmic grader pathway appears safe and cost saving. The sensitivity of the new pathway to detect active proliferative diabetic retinopathy was lower, but may still be considered acceptable for patients with proliferative diabetic retinopathy previously treated with laser. Suggestions from focus group discussions should be taken into consideration if the new pathway is introduced to ensure its acceptability to users. Limitations: Lack of fundus fluorescein angiography to confirm diagnosis of active proliferative diabetic retinopathy. Future work: Could refinement of the new pathway increase its sensitivity to detect proliferative diabetic retinopathy? Could artificial intelligence be used for automated reading of images in this previously treated population? Trial registration: Current Controlled Trials ISRCTN10856638 and ClinicalTrials.gov NCT03490318. 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. 32. See the NIHR Journals Library website for further project information.

AbstractBackgroundOutcome measurement in forensic mental health services can support service improvement, research, and patient progress evaluation. This systematic review aims to identify instruments available for use as outcome measures in this field and assess the evidence for the most common instruments, specific to the forensic context, which cover multiple outcome domains.MethodsStudies were identified by searching seven online databases. Additional searches were then performed for 10 selected instruments to identify additional information on their psychometric properties. Instrument manuals and gray literature was reviewed for information about instrument development and content validity. The quality of evidence for psychometric properties was summarized for each instrument based on the COnsensus-based Standards for health Measurement INstruments (COSMIN) approach.ResultsA total of 435 different instruments or variants were identified. Psychometric information on the 10 selected instruments was extracted from 103 studies. All 10 instruments had a clinician reported component with only two having patient reported scales. Half of the instruments were primarily focused on risk. No instrument demonstrated adequate psychometric properties in all eight COSMIN categories assessed. Only one instrument, the Camberwell Assessment of Need: Forensic Version, had adequate evidence for its development and content validity. The most evidence was for construct validity, while none was identified for construct stability between groups.ConclusionsDespite the large number of instruments potentially available, evidence for their use as outcome measures in forensic mental health services is limited. Future research and instrument development should involve patients and carers to ensure adequate content validity.

Background: Men who suffer recurrence of bulbar urethral stricture have to decide between endoscopic urethrotomy and open urethroplasty to manage their urinary symptoms. Evidence of relative clinical effectiveness and cost-effectiveness is lacking. Objectives: To assess benefit, harms and cost-effectiveness of open urethroplasty compared with endoscopic urethrotomy as treatment for recurrent urethral stricture in men. Design: Parallel-group, open-label, patient-randomised trial of allocated intervention with 6-monthly follow-ups over 24 months. Target sample size was 210 participants providing outcome data. Participants, clinicians and local research staff could not be blinded to allocation. Central trial staff were blinded when needed. Setting: UK NHS with recruitment from 38 hospital sites. Participants: A total of 222 men requiring operative treatment for recurrence of bulbar urethral stricture who had received at least one previous intervention for stricture. Interventions: A centralised randomisation system using random blocks allocated participants 1 : 1 to open urethroplasty (experimental group) or endoscopic urethrotomy (control group). Main outcome measures: The primary clinical outcome was control of urinary symptoms. Cost-effectiveness was assessed by cost per quality-adjusted life-year (QALY) gained over 24 months. The main secondary outcome was the need for reintervention for stricture recurrence. Results: The mean difference in the area under the curve of repeated measurement of voiding symptoms scored from 0 (no symptoms) to 24 (severe symptoms) between the two groups was –0.36 [95% confidence interval (CI) –1.78 to 1.02; p = 0.6]. Mean voiding symptom scores improved between baseline and 24 months after randomisation from 13.4 [standard deviation (SD) 4.5] to 6 (SD 5.5) for urethroplasty group and from 13.2 (SD 4.7) to 6.4 (SD 5.3) for urethrotomy. Reintervention was less frequent and occurred earlier in the urethroplasty group (hazard ratio 0.52, 95% CI 0.31 to 0.89; p = 0.02). There were two postoperative complications requiring reinterventions in the group that received urethroplasty and five, including one death from pulmonary embolism, in the group that received urethrotomy. Over 24 months, urethroplasty cost on average more than urethrotomy (cost difference £2148, 95% CI £689 to £3606) and resulted in a similar number of QALYs (QALY difference –0.01, 95% CI –0.17 to 0.14). Therefore, based on current evidence, urethrotomy is considered to be cost-effective. Limitations: We were able to include only 69 (63%) of the 109 men allocated to urethroplasty and 90 (80%) of the 113 men allocated to urethrotomy in the primary complete-case intention-to-treat analysis. Conclusions: The similar magnitude of symptom improvement seen for the two procedures over 24 months of follow-up shows that both provide effective symptom control. The lower likelihood of further intervention favours urethroplasty, but this had a higher cost over the 24 months of follow-up and was unlikely to be considered cost-effective. Future work: Formulate methods to incorporate short-term disutility data into cost-effectiveness analysis. Survey pathways of care for men with urethral stricture, including the use of enhanced recovery after urethroplasty. Establish a pragmatic follow-up schedule to allow national audit of outcomes following urethral surgery with linkage to NHS Hospital Episode Statistics. Trial registration: Current Controlled Trials ISRCTN98009168. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 61. See the NIHR Journals Library website for further project information.

Objectives To estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool.Design Retrospective analysis of medical records and decision tree model evaluating policy changes using local and national data.Setting One musculoskeletal interface clinic (hub) in England.Participants 922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis.Interventions We assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced.Main outcome measure OKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years.Results Of 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1–41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5–44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year.Conclusions Musculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.

Background and purpose — There is a need to understand the reasons why a high proportion of rotator cuff repairs fail to heal. Using data from a large randomized clinical trial, we evaluated age and tear size as risk factors for failure of rotator cuff repair. Patients and methods — Between 2007 and 2014, 65 surgeons from 47 hospitals in the National Health Service (NHS) recruited 447 patients with atraumatic rotator cuff tendon tears to the United Kingdom Rotator Cuff Trial (UKUFF) and 256 underwent rotator cuff repair. Cuff integrity was assessed by imaging in 217 patients, at 12 months post-operation. Logistic regression analysis was used to determine the influence of age and intra-operative tear size on healing. Hand dominance, sex, and previous steroid injections were controlled for. Results — The overall healing rate was 122/217 (56%) at 12 months. Healing rate decreased with increasing tear size (small tears 66%, medium tears 68%, large tears 47%, and massive tears 27% healed). The mean age of patients with a healed repair was 61 years compared with 64 years for those with a non-healed repair. Mean age increased with larger tear sizes (small tears 59 years, medium tears 62 years, large tears 64 years, and massive tears 66 years). Increasing age was an independent factor that negatively influenced healing, even after controlling for tear size. Only massive tears were an independent predictor of non-healing, after controlling for age. Interpretation — Although increasing age and larger tear size are both risks for failure of rotator cuff repair healing, age is the dominant risk factor.

Abstract Background Temporal changes in the placebo arm of randomized controlled trials (RCTs) have not been thoroughly investigated, despite the fact that results of RCTs depend on the comparison between arms. Methods In this update of our earlier systematic review and meta-analysis, we set out to investigate the effect of assessment time and number of visits on the magnitude of change from baseline in the placebo arm of these trials. We used linear mixed-effects models to account for within-trial correlations. Results Across all 47 trials the magnitude of response in the placebo arm did not change with time (β = -0.0070, 95% CI -0.024, 0.010) or visit (β = -0.033, 95% CI -0.082, 0.017) and remained significantly different from baseline for at least 12 months or seven follow-up visits. Change in the placebo arm in trials with subjective outcomes was large (β0 = 0.68, 95% CI 0.53, 0.82) and relatively constant across time (β = -0.0042, 95% CI -0.024, 0.016) and visit (β = -0.029, 95% CI -0.089, 0.031), whereas in trials with objective outcomes the response was smaller (β0 = 0.28, 95% CI 0.11, 0.46) and diminished with time (β = -0.030, 95% CI -0.050, -0.010), but not with visit (β = -0.099, 95% CI -0.30, 0.11). For trials with assessed outcomes, there was no significant effect of time (β = -0.0071, 95% CI -0.026, 0.011) or visit (β = -0.032, 95% CI -0.33, 0.26); however, these results should be interpreted with caution due to the small number of studies, and high clinical heterogeneity between studies. In trials with pain as an outcome, the improvement was significant (β0 = 0.91, 95% CI 0.75, 1.07), but there was no effect of time (β = -0.013, 95% CI -0.06, 0.03) or visit (β = -0.045, 95% CI -0.16, 0.069), and pain ratings remained significantly different from baseline for 12 months or seven visits. Conclusions These results are consistent with our previous findings. In trials with subjective outcomes response in the placebo arm remains large and relatively constant for at least a year, which is interesting considering that this is an effect of a single application of an invasive procedure. The lack of effect of time and visit number on subjective outcomes raises further questions regarding whether the observed response is the result of placebo effect or the result of bias.

Abstract Background Carpal tunnel syndrome (CTS) is the commonest peripheral nerve disorder in the UK, with over 52,996 carpal tunnel decompressions performed in 2011. By 2030, this figure is estimated to double. Whilst evidence supports conservative measures for mild symptoms, and early surgery for severe symptoms, controversy remains over the most appropriate management for patients that present with moderate disease, with regard to early surgery or late surgery following steroid injection. Injection versus Decompression for Carpal Tunnel Syndrome-Pilot trial (INDICATE-P) is a feasibility study for a multicentre, randomised controlled trial (INDICATE) to determine whether patients over the age of 18 with moderate CTS should undergo early surgical decompression of the median nerve or a single steroid injection (followed by later surgery if required). Methods/design INDICATE-P is a feasibility study for an open (non-blinded) randomised controlled pilot trial. Eligible participants will be adults with a clinical diagnosis of moderate CTS. This is defined as symptoms disturbing sleep or restricting activities of daily living or work, despite a 2-week trial of night splints. Participants will be randomised to one of two possible interventions: surgical decompression or a single steroid injection (followed by surgery later if required). Clinical outcome measures will be captured by postal questionnaire at 1, 3, 6 and 12 months post-randomisation. In order to improve the study design for the main INDICATE trial, feasibility data will also be collected to identify difficulties in recruitment and retention, to gain patient feedback on questionnaires and to confirm the suitability of the proposed outcome measures. Discussion The INDICATE-P feasibility study will contribute to the design and execution of the INDICATE trial, which will seek to assess the safety and effectiveness of two approaches to treatment for patients over 18 years of age with moderate CTS: early carpal tunnel decompression or a single steroid injection (followed by later surgery).

The Cx26 mRNA has not been reported to undergo alternative splicing. In expressing a series of human keratitis ichthyosis deafness (KID) syndrome mutations of Cx26 (A88V, N14K and A40V), we found the production of a truncated mRNA product. These mutations, although not creating a cryptic splice site, appeared to activate a pre-existing cryptic splice site. The alternative splicing of the mutant Cx26 mRNA could be prevented by mutating the predicted 3′, 5′ splice sites and the branch point. The presence of a C-terminal fluorescent protein tag (mCherry or Clover) was necessary for this alternative splicing to occur. Strangely, Cx26A88V could cause the alternative splicing of co-expressed WT Cx26—suggesting a trans effect. The alternative splicing of Cx26A88V caused cell death, and this could be prevented by the 3′, 5′ and branch point mutations. Expression of the KID syndrome mutants could be rescued by combining them with removal of the 5′ splice site. We used this strategy to enable expression of Cx26A40V-5′ and demonstrate that this KID syndrome mutation removed CO2 sensitivity from the Cx26 hemichannel. This is the fourth KID syndrome mutation found to abolish the CO2-sensitivity of the Cx26 hemichannel, and suggests that the altered CO­2-sensitivity could contribute to the pathology of this mutation. Future research on KID syndrome mutations should take care to avoid using a C-terminal tag to track cellular localization and expression or if this is unavoidable, combine this mutation with removal of the 5′ splice site.

Background: There is no good evidence to support the use of patient-reported outcome measures (PROMs) in setting preoperative thresholds for referral for hip and knee replacement surgery. Despite this, the practice is widespread in the NHS. Objectives/research questions: Can clinical outcome tools be used to set thresholds for hip or knee replacement? What is the relationship between the choice of threshold and the cost-effectiveness of surgery? Methods: A systematic review identified PROMs used to assess patients undergoing hip/knee replacement. Their measurement properties were compared and supplemented by analysis of existing data sets. For each candidate score, we calculated the absolute threshold (a preoperative level above which there is no potential for improvement) and relative thresholds (preoperative levels above which individuals are less likely to improve than others). Owing to their measurement properties and the availability of data from their current widespread use in the NHS, the Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were selected as the most appropriate scores to use in developing the Arthroplasty Candidacy Help Engine (ACHE) tool. The change in score and the probability of an improvement were then calculated and modelled using preoperative and postoperative OKS/OHSs and PROM scores, thereby creating the ACHE tool. Markov models were used to assess the cost-effectiveness of total hip/knee arthroplasty in the NHS for different preoperative values of OKS/OHSs over a 10-year period. The threshold values were used to model how the ACHE tool may change the number of referrals in a single UK musculoskeletal hub. A user group was established that included patients, members of the public and health-care representatives, to provide stakeholder feedback throughout the research process. Results: From a shortlist of four scores, the OHS and OKS were selected for the ACHE tool based on their measurement properties, calculated preoperative thresholds and cost-effectiveness data. The absolute threshold was 40 for the OHS and 41 for the OKS using the preferred improvement criterion. A range of relative thresholds were calculated based on the relationship between a patient’s preoperative score and their probability of improving after surgery. For example, a preoperative OHS of 35 or an OKS of 30 translates to a 75% probability of achieving a good outcome from surgical intervention. The economic evaluation demonstrated that hip and knee arthroplasty cost of

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species.

Visual design, learning sciences, and nanotechnology may be strange bedfellows; yet, as this paper highlights, peer interaction between a designer and a scientist is an effective method for helping scientists acquire visual design skills. We describe our findings from observing twelve sessions at the Design Help Desk, a tutoring center at the University of Washington. At each session, a scientist (who is expert in his own domain but a novice in design) consulted a designer (who is expert in design but a novice in science) in order to receive advice and guidance on how to improve a scientific visualization. At the Design Help Desk, this pairing consistently produced a momentary disequilibrium in the scientist's thought process: a disequilibrium that led to agency (where the scientist gained ownership of his/her own learning) and conceptual change in the scientist's understanding of visual design. Scientists who visited the Design Help Desk were satisfied with their experience, and their published work demonstrated an improved ability to visually communicate research findings-a skill critical to the advancement of science. To our knowledge, the Design Help Desk is a unique effort to educate scientists in visual design; we are not aware of any other design-advice/tutoring centers at public or private universities in the United States or abroad.

Background: Haemorrhoids are a benign anorectal condition and are highly prevalent in the UK population. Treatments involve clinic-based procedures and surgery. The surgical procedures available include stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH), and over 25,000 operations are performed for haemorrhoids annually in the UK. The disease is therefore important both to patients and to health service commissioners. Debate remains as to which of these surgical procedures is the most clinically effective and cost-effective. Objective: The aim of this study was to compare the clinical effectiveness and cost-effectiveness of SH with that of TH. Design: A large, open two-arm parallel-group pragmatic multicentre randomised controlled trial involving 32 UK hospitals and a within-trial cost–benefit analysis. A discrete choice experiment was conducted to estimate benefits (willingness to pay). Participants: Patients with grades II–IV haemorrhoids who had not previously undergone SH or TH were included in the study. Interventions: Participants were randomised to receive either SH or TH. Randomisation was minimised at 1 : 1, in accordance with baseline EuroQol-5 Dimensions, three-level version (EQ-5D-3L) score, haemorrhoid grade, sex and centre, via an automated system. Main outcome measures: The primary outcome was area under the quality-of-life curve measured using the EQ-5D-3L descriptive system over 24 months, and the primary economic outcome was the incremental cost-effectiveness ratio. Secondary outcomes included disease-specific quality of life, recurrence, complications, further interventions and costs. Results: Between January 2011 and August 2014, 777 patients were randomised (389 to receive SH and 388 to receive TH). There were 774 participants included in the analysis as a result of one post-randomisation exclusion in the SH arm and two in the TH arm. SH was less painful than TH in the short term. Surgical complications were similar in both arms. EQ-5D-3L score was higher for the SH arm in the first 6 weeks after surgery, but over 24 months the TH group had significantly better EQ-5D-3L scores (–0.073, 95% confidence interval –0.140 to –0.006; p = 0.0342). Symptoms and further interventions were significantly fewer in the TH arm at 24 months. Continence was better in the TH arm and tenesmus occurred less frequently. The number of serious adverse events reported was 24 out of 337 (7.1%) for participants who received SH and 33 out of 352 (9.4%) for those who received TH. There were two deaths in the SH arm, both unrelated to the eTHoS (either Traditional Haemorrhoidectomy or Stapled haemorrhoidopexy for haemorrhoidal disease) study. Patient preference did not seem to influence the treatment difference. SH was dominated by TH as it cost more and was less effective. The net benefit for the TH arm was higher than that for the SH arm. Limitations: Neither the participants nor the assessors were masked to treatment assignment and final recruitment was slightly short of the total target of 800. There were also substantial missing follow-up data. Conclusions: While patients who received SH had less short-term pain, after 6 weeks, recurrence rates, symptoms, re-interventions and quality-of-life measures all favoured TH. In addition, TH is cheaper. As part of a tailored management plan for haemorrhoids, TH should be considered over SH as the surgical treatment of choice for haemorrhoids refractory to clinic-based interventions. Future work: Perform an updated meta-analysis incorporating recently conducted European trials [eTHoS, HubBLe (haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids) and LingaLongo (Cost-effectiveness of New Surgical Treatments for Haemorrhoidal Disease)]. Trial registration: Current Controlled Trials ISRCTN80061723. 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. 21, No. 70. See the NIHR Journals Library website for further project information.

Background: Many glaucoma referrals from the community to hospital eye services are unnecessary. Imaging technologies can potentially be useful to triage this population. Objectives: To assess the diagnostic performance and cost-effectiveness of imaging technologies as triage tests for identifying people with glaucoma. Design: Within-patient comparative diagnostic accuracy study. Markov economic model comparing the cost-effectiveness of a triage test with usual care. Setting: Secondary care. Participants: Adults referred from the community to hospital eye services for possible glaucoma. Interventions: Heidelberg Retinal Tomography (HRT), including two diagnostic algorithms, glaucoma probability score (HRT-GPS) and Moorfields regression analysis (HRT-MRA); scanning laser polarimetry [glaucoma diagnostics (GDx)]; and optical coherence tomography (OCT). The reference standard was clinical examination by a consultant ophthalmologist with glaucoma expertise including visual field testing and intraocular pressure (IOP) measurement. Main outcome measures: (1) Diagnostic performance of imaging, using data from the eye with most severe disease. (2) Composite triage test performance (imaging test, IOP measurement and visual acuity measurement), using data from both eyes, in correctly identifying clinical management decisions, that is ‘discharge’ or ‘do not discharge’. Outcome measures were sensitivity, specificity and incremental cost per quality-adjusted life-year (QALY). Results: Data from 943 of 955 participants were included in the analysis. The average age was 60.5 years (standard deviation 13.8 years) and 51.1% were females. Glaucoma was diagnosed by the clinician in at least one eye in 16.8% of participants; 37.9% of participants were discharged after the first visit. Regarding diagnosing glaucoma, HRT-MRA had the highest sensitivity [87.0%, 95% confidence interval (CI) 80.2% to 92.1%] but the lowest specificity (63.9%, 95% CI 60.2% to 67.4%) and GDx had the lowest sensitivity (35.1%, 95% CI 27.0% to 43.8%) but the highest specificity (97.2%, 95% CI 95.6% to 98.3%). HRT-GPS had sensitivity of 81.5% (95% CI 73.9% to 87.6%) and specificity of 67.7% (95% CI 64.2% to 71.2%) and OCT had sensitivity of 76.9% (95% CI 69.2% to 83.4%) and specificity of 78.5% (95% CI 75.4% to 81.4%). Regarding triage accuracy, triage using HRT-GPS had the highest sensitivity (86.0%, 95% CI 82.8% to 88.7%) but the lowest specificity (39.1%, 95% CI 34.0% to 44.5%), GDx had the lowest sensitivity (64.7%, 95% CI 60.7% to 68.7%) but the highest specificity (53.6%, 95% CI 48.2% to 58.9%). Introducing a composite triage station into the referral pathway to identify appropriate referrals was cost-effective. All triage strategies resulted in a cost reduction compared with standard care (consultant-led diagnosis) but with an associated reduction in effectiveness. GDx was the least costly and least effective strategy. OCT and HRT-GPS were not cost-effective. Compared with GDx, the cost per QALY gained for HRT-MRA is £22,904. The cost per QALY gained with current practice is £156,985 compared with HRT-MRA. Large savings could be made by implementing HRT-MRA but some benefit to patients will be forgone. The results were sensitive to the triage costs. Conclusions: Automated imaging can be effective to aid glaucoma diagnosis among individuals referred from the community to hospital eye services. A model of care using a triage composite test appears to be cost-effective. Future work: There are uncertainties about glaucoma progression under routine care and the cost of providing health care. The acceptability of implementing a triage test needs to be explored. Funding: The National Institute for Health Research Health Technology Assessment programme.

Recombination in enteroviruses provides an evolutionary mechanism for acquiring extensive regions of novel sequence, is suggested to have a role in genotype diversity and is known to have been key to the emergence of novel neuropathogenic variants of poliovirus. Despite the importance of this evolutionary mechanism, the recombination process remains relatively poorly understood. We investigated heterologous recombination using a novel reverse genetic approach that resulted in the isolation of intermediate chimeric intertypic polioviruses bearing genomes with extensive duplicated sequences at the recombination junction. Serial passage of viruses exhibiting such imprecise junctions yielded progeny with increased fitness which had lost the duplicated sequences. Mutations or inhibitors that changed polymerase fidelity or the coalescence of replication complexes markedly altered the yield of recombinants (but did not influence non-replicative recombination) indicating both that the process is replicative and that it may be possible to enhance or reduce recombination-mediated viral evolution if required. We propose that extant recombinants result from a biphasic process in which an initial recombination event is followed by a process of resolution, deleting extraneous sequences and optimizing viral fitness. This process has implications for our wider understanding of 'evolution by duplication' in the positive-strand RNA viruses.

Mentorship programmes are popular for the development of black managers in South Africa. In the literature, controversy surrounds attempts to institutionalize mentorship. In this article it is argued that the concept of a learning partnership should replace that of mentorship, particularly in what are seen to be learning organizations. Many mentorship programmes are predicated on the belief that a warm and caring relationship is a prerequisite for effective development of protégés. Redefining the desired relationship as a learning partnership removes this demand on the relationship and places it squarely in the confines of a normal business affiliation in which the focus is mutual learning. Essential to the process of black advancement is empowerment. There are a number of dimensions to empowerment. In this article three key dimensions are discussed in relation to the development of black managers, namely objective power, subjective power and empowerment in competence. Based on insights gained in the initial phases of a mentorship programme implemented in a leading information technology company, a number of principles are offered for implementing learning partnerships in a learning organization. These revolve around the need to use a new paradigm to interpret the learning experiences that constitute a developmental relationship between a young and promising employee and a more experienced and knowledgeable manager.