Cost-effectiveness analysis of a pragmatic randomized trial evaluating surgical reconstruction versus rehabilitation in patients with long-standing anterior cruciate ligament injury.

Aims: The aim of this study was to estimate the incremental use of resources, costs, and quality of life outcomes associated with surgical reconstruction compared to rehabilitation for long-standing anterior cruciate ligament (ACL) injury in the NHS, and to estimate its cost-effectiveness. Methods: A total of 316 patients were recruited and randomly assigned to either surgical reconstruction or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment). Healthcare resource use and health-related quality of life data (EuroQol five-dimension five-level health questionnaire) were collected in the trial at six, 12, and 18 months using self-reported questionnaires and medical records. Using intention-to-treat analysis, differences in costs, and quality-adjusted life years (QALYs) between treatment arms were estimated adjusting for baseline differences and following multiple imputation of missing data. The incremental cost-effectiveness ratio (ICER) was estimated as the difference in costs divided by the difference in QALYs between reconstruction and rehabilitation. Results: At 18 months, patients in the surgical reconstruction arm reported higher QALYs (0.052 (95% confidence interval (CI) -0.012 to 0.117); p = 0.177) and higher NHS costs (£1,017 (95% CI 557 to 1,476); p < 0.001) compared to rehabilitation. This resulted in an ICER of £19,346 per QALY with the probability of surgical reconstruction being cost-effective of 51% and 72% at a willingness-to-pay threshold of £20,000 and £30,000 per QALY, respectively. Conclusion: Surgical reconstruction as a management strategy for patients with long-standing ACL injury is more effective, but more expensive, at 18 months compared to rehabilitation management. In the UK setting, surgical reconstruction is cost-effective.

Cost-effectiveness of replacing versus discarding the nail in children with nail bed injury.

Every year in the UK, around 10 000 children need to have operations to mend injuries to the bed of their fingernails. Currently, most children have their fingernail placed back on the injured nail bed after the operation. The NINJA trial found that children were slightly less likely to have an infection if the nail was thrown away rather than being put back, but the difference between groups was small and could have be due to chance. This study looked at whether replacing the nail is cost-effective compared with throwing it away. Using data from the NINJA trial, we compared costs, healthcare use, and quality of life and assessed the cost-effectiveness of replacing the nail. It was found that throwing the nail away after surgery would save the National Health Service (NHS) £75 (€85) per operation compared with placing the nail back on the nail bed. Changing clinical practice could save the NHS in England £720 000 (€819 000) per year.

Effectiveness of nail bed repair in children with or without replacing the fingernail: NINJA multicentre randomized clinical trial.

BACKGROUND: Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. METHODS: A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. RESULTS: Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was €84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm (P < 0.001). CONCLUSION: After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving. Registration number: ISRCTN44551796 (http://www.controlled-trials.com).

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial.

BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.

A longitudinal assessment of trial protocols approved by research ethics committees: The Adherance to SPIrit REcommendations in the UK (ASPIRE-UK) study.

BACKGROUND: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. METHODS: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. RESULTS: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6-69.2%) in 2012 to a median of 72.5% (IQR, 65.3-78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1-69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5-67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2-79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6-76.3%). CONCLUSIONS: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.

ACL Surgery Necessity in Non-Acute Patients (ACL SNNAP): a statistical analysis plan for a randomised controlled trial.

BACKGROUND: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries. METHODS/DESIGN: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously. DISCUSSION: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results. TRIAL REGISTRATION: ISRCTN ISRCTN10110685 . Registered on 16 November 2016.

Efficacy of Liposomal Bupivacaine and Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Periarticular Anesthetic for Patients Undergoing Knee Replacement: A Randomized Clinical Trial.

Importance: More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain. Objective: To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement. Design, Setting, and Participants: This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. Interventions: Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery. Main Outcome and Measures: The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed. Results: Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, -2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5% CI, -46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5% CI, -1.07 to -0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups. Conclusions and Relevance: This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery. Trial Registration: isrctn.com Identifier: ISRCTN54191675.

Surgical interventions for treating extracapsular hip fractures in older adults: a network meta-analysis.

BACKGROUND: Hip fractures are a major healthcare problem, presenting a challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising. The majority of extracapsular hip fractures are treated surgically. OBJECTIVES: To assess the relative effects (benefits and harms) of all surgical treatments used in the management of extracapsular hip fractures in older adults, using a network meta-analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Web of Science and five other databases in July 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing different treatments for fragility extracapsular hip fractures in older adults. We included internal and external fixation, arthroplasties and non-operative treatment. We excluded studies of hip fractures with specific pathologies other than osteoporosis or resulting from high-energy trauma. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health-related quality of life (HRQoL) - both reported within 4 months, at 12 months and after 24 months of surgery, and unplanned return to theatre (at end of study follow-up). We performed a network meta-analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. MAIN RESULTS: We included 184 studies (160 RCTs and 24 quasi-RCTs) with 26,073 participants with 26,086 extracapsular hip fractures in the review. The mean age in most studies ranged from 60 to 93 years, and 69% were women. After discussion with clinical experts, we selected nine nodes that represented the best balance between clinical plausibility and efficiency of the networks: fixed angle plate (dynamic and static), cephalomedullary nail (short and long), condylocephalic nail, external fixation, hemiarthroplasty, total hip arthroplasty (THA) and non-operative treatment. Seventy-three studies (with 11,126 participants) with data for at least two of these treatments contributed to the NMA. We selected the dynamic fixed angle plate as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison.  We downgraded the certainty of the evidence for serious and very serious risks of bias, and because some of the estimates included the possibility of transitivity owing to the proportion of stable and unstable fractures between treatment comparisons. We also downgraded if we noted evidence of inconsistency in direct or indirect estimates from which the network estimate was derived. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision.  Overall, 20.2% of participants who received the reference treatment had died by 12 months after surgery. We noted no evidence of any differences in mortality at this time point between the treatments compared. Effect estimates of all treatments included plausible benefits as well as harms. Short cephalomedullary nails had the narrowest confidence interval (CI), with 7 fewer deaths (26 fewer to 15 more) per 1000 participants, compared to the reference treatment (risk ratio (RR) 0.97, 95% CI 0.87 to 1.07). THA had the widest CI, with 62 fewer deaths (177 fewer to 610 more) per 1000 participants, compared to the reference treatment (RR 0.69, 95% CI 0.12 to 4.03). The certainty of the evidence for all treatments was low to very low. Although we ranked the treatments, this ranking should be interpreted cautiously because of the imprecision in all the network estimates for these treatments. Overall, 4.3% of participants who received the reference treatment had unplanned return to theatre. Compared to this treatment, we found very low-certainty evidence that 58 more participants (14 to 137 more) per 1000 participants returned to theatre if they were treated with a static fixed angle plate (RR 2.48, 95% CI 1.36 to 4.50), and 91 more participants (37 to 182 more) per 1000 participants returned to theatre if treated with a condylocephalic nail (RR 3.33, 95% CI 1.95 to 5.68). We also found that these treatments were ranked as having the highest probability of unplanned return to theatre. In the remaining treatments, we noted no evidence of any differences in unplanned return to theatre, with effect estimates including benefits as well as harms. The certainty of the evidence for these other treatments ranged from low to very low. We did not use GRADE to assess the certainty of the evidence for early mortality, but our findings were similar to those for 12-month mortality, with no evidence of any differences in treatments when compared to dynamic fixed angle plate. Very few studies reported HRQoL and we were unable to build networks from these studies and perform network meta-analysis.  AUTHORS' CONCLUSIONS: Across the networks, we found that there was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, static implants such as condylocephalic nails and static fixed angle plates did yield a higher risk of unplanned return to theatre. We had insufficient evidence to determine the effects of any treatments on HRQoL, and this review includes data for only two outcomes. More detailed pairwise comparisons of some of the included treatments are reported in other Cochrane Reviews in this series. Short cephalomedullary nails versus dynamic fixed angle plates contributed the most evidence to each network, and our findings indicate that there may be no difference between these treatments. These data included people with both stable and unstable extracapsular fractures. At this time, there are too few studies to draw any conclusions regarding the benefits or harms of arthroplasty or external fixation for extracapsular fracture in older adults. Future research could focus on the benefits and harms of arthroplasty interventions compared with internal fixation using a dynamic implant.

Surgical interventions for treating intracapsular hip fractures in older adults: a network meta-analysis.

BACKGROUND: Hip fractures are a major healthcare problem, presenting a considerable challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising rapidly. The majority of intracapsular hip fractures are treated surgically. OBJECTIVES: To assess the relative effects (benefits and harms) of all surgical treatments used in the management of intracapsular hip fractures in older adults, using a network meta-analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Web of Science, and five other databases in July 2020. We also searched clinical trials databases, conference proceedings, reference lists of retrieved articles and conducted backward-citation searches. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing different treatments for fragility intracapsular hip fractures in older adults. We included total hip arthroplasties (THAs), hemiarthroplasties (HAs), internal fixation, and non-operative treatments. We excluded studies of people with hip fracture with specific pathologies other than osteoporosis or resulting from high-energy trauma. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health-related quality of life (HRQoL) - both reported within 4 months, at 12 months, and after 24 months of surgery, and unplanned return to theatre (at end of study follow-up). We performed a network meta-analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. MAIN RESULTS: We included 119 studies (102 RCTS, 17 quasi-RCTs) with 17,653 participants with 17,669 intracapsular fractures in the review; 83% of fractures were displaced. The mean participant age ranged from 60 to 87 years and 73% were women.  After discussion with clinical experts, we selected 12 nodes that represented the best balance between clinical plausibility and efficiency of the networks: cemented modern unipolar HA, dynamic fixed angle plate, uncemented first-generation bipolar HA, uncemented modern bipolar HA, cemented modern bipolar HA, uncemented first-generation unipolar HA, uncemented modern unipolar HA, THA with single articulation, dual-mobility THA, pins, screws, and non-operative treatment. Seventy-five studies (with 11,855 participants) with data for at least two of these treatments contributed to the NMA. We selected cemented modern unipolar HA as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison. In order to provide a concise summary of the results, we report only network estimates when there was evidence of difference between treatments. We downgraded the certainty of the evidence for serious and very serious risks of bias and when estimates included possible transitivity, particularly for internal fixation which included more undisplaced fractures. We also downgraded for incoherence, or inconsistency in indirect estimates, although this affected few estimates. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision.  We found that cemented modern unipolar HA, dynamic fixed angle plate and pins seemed to have the greatest likelihood of reducing mortality at 12 months. Overall, 23.5% of participants who received the reference treatment died within 12 months of surgery. Uncemented modern bipolar HA had higher mortality than the reference treatment (RR 1.37, 95% CI 1.02 to 1.85; derived only from indirect evidence; low-certainty evidence), and THA with single articulation also had higher mortality (network estimate RR 1.62, 95% CI 1.13 to 2.32; derived from direct evidence from 2 studies with 225 participants, and indirect evidence; very low-certainty evidence). In the remaining treatments, the certainty of the evidence ranged from low to very low, and we noted no evidence of any differences in mortality at 12 months.  We found that THA (single articulation), cemented modern bipolar HA and uncemented modern bipolar HA seemed to have the greatest likelihood of improving HRQoL at 12 months. This network was comparatively sparse compared to other outcomes and the certainty of the evidence of differences between treatments was very low. We noted no evidence of any differences in HRQoL at 12 months, although estimates were imprecise. We found that arthroplasty treatments seemed to have a greater likelihood of reducing unplanned return to theatre than internal fixation and non-operative treatment. We estimated that 4.3% of participants who received the reference treatment returned to theatre during the study follow-up. Compared to this treatment, we found low-certainty evidence that more participants returned to theatre if they were treated with a dynamic fixed angle plate (network estimate RR 4.63, 95% CI 2.94 to 7.30; from direct evidence from 1 study with 190 participants, and indirect evidence). We found very low-certainty evidence that more participants returned to theatre when treated with pins (RR 4.16, 95% CI 2.53 to 6.84; only from indirect evidence), screws (network estimate RR 5.04, 95% CI 3.25 to 7.82; from direct evidence from 2 studies with 278 participants, and indirect evidence), and non-operative treatment (RR 5.41, 95% CI 1.80 to 16.26; only from indirect evidence). There was very low-certainty evidence of a tendency for an increased risk of unplanned return to theatre for all of the arthroplasty treatments, and in particular for THA, compared with cemented modern unipolar HA, with little evidence to suggest the size of this difference varied strongly between the arthroplasty treatments. AUTHORS' CONCLUSIONS: There was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, cemented modern arthroplasties tended to more often yield better outcomes than alternative treatments and may be a more successful approach than internal fixation. There is no evidence of a difference between THA (single articulation) and cemented modern unipolar HA in the outcomes measured in this review. THA may be an appropriate treatment for a subset of people with intracapsular fracture but we have not explored this further.

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): statistical analysis plan for a randomised controlled trial assessing the effectiveness of peri-articular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone.

BACKGROUND: Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement. METHODS/DESIGN: The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published. RESULTS: The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests. DISCUSSION: The paper provides details of the planned statistical analyses for the SPAARK trial and aims to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report. TRIAL REGISTRATION: ISRCTN54191675 . Registered on 13 November 2017.

Reamed intramedullary nailing versus circular frame external fixation for segmental tibial fractures (STIFF-F): a mixed methods feasibility study.

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.

The Oxford Finger Nail Appearance Score - a new scoring system for fingernail deformity following paediatric finger tip trauma.

Fingernail deformity is common, yet current methods used to define cosmetic appearance following trauma are mainly descriptive. In order to quantify the cosmetic appearance of the fingernail, we developed the Oxford Fingernail Appearance Score using a three stage iterative process. The score has five cosmetic components marked as binary outcomes composed of nail shape, nail adherence, eponychial appearance, nail surface appearance and presence of a split. In the first stage, two assessors independently assessed 25 photographs of fingernails taken at a minimum of four months following paediatric nail bed repair and compared them to the corresponding contralateral uninjured finger. Following refinement in the score, ten different assessors scored a further 62 photographs of fingernails taken after paediatric nail bed repair. Assessors completed each of the five components, and the overall component score was calculated by statisticians post-hoc, taking the ideal appearance of each component as 1 ("identical to opposite" for nail shape, eponychium and surface, "complete" for adherence, "absent" for split) and all the non-ideal appearances as 0. Assessors effectively scored the photographs' integer values between 0 (least optimal appearance) and 5 (most optimal appearance). Refinements in the scoring system resulted in an improvement in a weighted kappa statistic of 0.36 (95% CI:0.09,0.68) in the initial score to 0.52 (95% CI: 0.42, 0.61). The Oxford Fingernail Appearance Score is a user-friendly and reliable scoring system which has application in a clinical trial setting.

Should the nail plate be replaced or discarded after nail bed repair in children? Nail bed INJury Analysis (NINJA) randomised controlled trial: a health economic and statistical analysis plan.

BACKGROUND: Nail bed trauma is one of the most common surgically treated paediatric hand injuries in the UK. Despite surgeons generally expressing a preference to replace the nail plate after repairing the nail bed, there is limited evidence to support this practice. We describe a statistical and health economic analysis plan (SHEAP) for the Nail bed INJury Analysis (NINJA) randomised controlled trial. METHODS/DESIGN: NINJA is a multicentre, pragmatic, superiority, parallel group randomised controlled trial of the treatment of nail bed injury in participants 16 years old or younger. The study aims to evaluate the efficacy and cost-effectiveness of replacing the nail plate compared to discarding it following the repair of a nail bed injury. Surgical site infection at 7-10 days post-randomisation and cosmetic appearance of the nail are the co-primary outcomes for NINJA. Surgical site infection at 7-10 days post-randomisation will be evaluated using a logistic regression model adjusting for site as the sole stratification factor and allowing for intra-site correlation. Cosmetic appearance will be assessed via the newly developed Oxford Finger Nail Appearance Score and will be evaluated by use of a Mann-Whitney U test. An ordinal logistic regression model will also be used to assess the Oxford Finger Nail Appearance Score, adjusting for site and allowing for intra-site correlation. Secondary outcomes are measured at 7-10 days and 4 months and include the EQ-5D-Y questionnaire, pain at first dressing change, cost-effectiveness, late surgical site infection, and participant/parent satisfaction with nail healing. Missing primary outcome data will be summarised by treatment arm and investigated through a sensitivity analysis. Full details of the planned methods of analysis and descriptive statistics are described in this paper. The NINJA study protocol has been published previously. DISCUSSION: The planned analysis strategy for the NINJA trial has been set out here to reduce the risk of reporting bias and data-driven analysis. Any deviations from the SHEAP described in this paper will be detailed and justified fully in the final report of the trial. TRIAL REGISTRATION: ISRCTN, ISRCTN44551796 . Registered on 23 April 2018.

Regioselective Amidomethylation of 4-Chloro-3-fluoropyridine by Metalation and Minisci-Type Reactions.

The synthesis of a series of 2-amidomethylated pyridines (3-8) was investigated, starting from 4-chloro-3-fluoropyridine. Kinetic deprotonation at -75 °C followed by reaction with DMF gave 2-formyl-4-chloro-3-fluoropyridine 10 regioselectively, which was converted to 2-aminomethyl analogue 1 via sulfinamide 2. Alternatively, Minisci-type amidomethylation under Ag+/persulfate or photoredox-mediated conditions using a series of amino acid derivatives gave (3-8, 19, and 34) in 30-74% yield and isomer ratios in the range 6.7:1 to >50:1. The latter methods gave overall yields similar to that of the deprotonation approach, but were shorter and more amenable to scale-up. In particular, N-Boc analogue 8 was obtained in a single step. The amidomethylations of another six 3-fluoropyridines under the photoredox conditions were briefly examined.

Current practice in analysing and reporting binary outcome data-a review of randomised controlled trial reports.

BACKGROUND: Randomised controlled trials (RCTs) need to be reported so that their results can be unambiguously and robustly interpreted. Binary outcomes yield unique challenges, as different analytical approaches may produce relative, absolute, or no treatment effects, and results may be particularly sensitive to the assumptions made about missing data. This review of recently published RCTs aimed to identify the methods used to analyse binary primary outcomes, how missing data were handled, and how the results were reported. METHODS: Systematic review of reports of RCTs published in January 2019 that included a binary primary outcome measure. We identified potentially eligible English language papers on PubMed, without restricting by journal or medical research area. Papers reporting the results from individually randomised, parallel-group RCTs were included. RESULTS: Two hundred reports of RCTs were included in this review. We found that 64% of the 200 reports used a chi-squared-style test as their primary analytical method. Fifty-five per cent (95% confidence interval 48% to 62%) reported at least one treatment effect measure, and 38% presented only a p value without any treatment effect measure. Missing data were not always adequately described and were most commonly handled using available case analysis (69%) in the 140 studies that reported missing data. Imputation and best/worst-case scenarios were used in 21% of studies. Twelve per cent of articles reported an appropriate sensitivity analysis for missing data. CONCLUSIONS: The statistical analysis and reporting of treatment effects in reports of randomised trials with a binary primary endpoint requires substantial improvement. Only around half of the studied reports presented a treatment effect measure, hindering the understanding and dissemination of the findings. We also found that published trials often did not clearly describe missing data or sensitivity analyses for these missing data. Practice for secondary endpoints or observational studies may differ.

NINJA trial: should the nail plate be replaced or discarded after nail bed repair in children? Protocol for a multicentre randomised control trial.

INTRODUCTION: Trauma to the nail bed is the most common surgically treated paediatric hand injury. The majority of surgeons replace the nail plate after repairing the nail bed despite a lack of evidence to do so. Replacing the nail plate may be associated with increased postoperative infection. We will investigate the impact of replacing or discarding the nail plate on infection, cosmetic appearance, pain and subsequent healthcare use. The Nail bed INJury Analysis trial (NINJA) aims to answer the question of whether the nail plate should be replaced or discarded after surgical nail bed repair in children. METHODS AND ANALYSIS: A two-arm parallel group open multicentre randomised control trial of replacing the nail plate or not, as part of a nail bed repair, will be undertaken in children presenting within 48 hours of a nail bed injury requiring surgical repair. The coprimary outcomes are: cosmetic appearance summary score at a minimum of 4 months and surgical site infection at around 7 days following surgery. Secondary outcomes are EuroQol EQ-5D-(Y); the pain intensity experienced at first dressing change; child/parent satisfaction with nail healing and healthcare resource use. We will recruit a minimum of 416 patients (208 in each group) over 3 years. Children and their parents/carers will be reviewed in clinic around 7 days after their operation and will be assessed for surgical site infection or other problems. The children, or depending on age, their parents/carers, will also be asked to complete a questionnaire and send in photos of their fingernail at a minimum of 4 months postsurgery to assess cosmetic appearance. ETHICS AND DISSEMINATION: The South Central Research Ethics Committee approved this study on 4 June 2019 (18/SC/0024). A manuscript to a peer-reviewed journal will be submitted on completion of the trial as per National Institute for Health Research publication policy. The results of this trial will substantially inform clinical practice and provide evidence on whether the practice of replacing the nail plate should continue at the time of nail bed repair. TRIAL REGISTRATION NUMBER: ISRCTN44551796.

A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation.

The human polo-like kinase PLK1 coordinates mitotic chromosome segregation by phosphorylating multiple chromatin- and kinetochore-binding proteins. How PLK1 activity is directed to specific substrates via phosphopeptide recognition by its carboxyl-terminal polo-box domain (PBD) is poorly understood. Here, we combine molecular, structural and chemical biology to identify a determinant for PLK1 substrate recognition that is essential for proper chromosome segregation. We show that mutations ablating an evolutionarily conserved, Tyr-lined pocket in human PLK1 PBD trigger cellular anomalies in mitotic progression and timing. Tyr pocket mutations selectively impair PLK1 binding to the kinetochore phosphoprotein substrate PBIP1, but not to the centrosomal substrate NEDD1. Through a structure-guided approach, we develop a small-molecule inhibitor, Polotyrin, which occupies the Tyr pocket. Polotyrin recapitulates the mitotic defects caused by mutations in the Tyr pocket, further evidencing its essential function, and exemplifying a new approach for selective PLK1 inhibition. Thus, our findings support a model wherein substrate discrimination via the Tyr pocket in the human PLK1 PBD regulates mitotic chromosome segregation to preserve genome integrity.

Antiplasmodial and trypanocidal activity of violacein and deoxyviolacein produced from synthetic operons.

BACKGROUND: Violacein is a deep violet compound that is produced by a number of bacterial species. It is synthesized from tryptophan by a pathway that involves the sequential action of 5 different enzymes (encoded by genes vioA to vioE). Violacein has antibacterial, antiparasitic, and antiviral activities, and also has the potential of inducing apoptosis in certain cancer cells. RESULTS: Here, we describe the construction of a series of plasmids harboring the complete or partial violacein biosynthesis operon and their use to enable production of violacein and deoxyviolacein in E.coli. We performed in vitro assays to determine the biological activity of these compounds against Plasmodium, Trypanosoma, and mammalian cells. We found that, while deoxyviolacein has a lower activity against parasites than violacein, its toxicity to mammalian cells is insignificant compared to that of violacein. CONCLUSIONS: We constructed E. coli strains capable of producing biologically active violacein and related compounds, and propose that deoxyviolacein might be a useful starting compound for the development of antiparasite drugs.

Determining molecular orientation via single molecule SERS in a plasmonic nano-gap.

In this work, plasmonic nano-gaps consisting of a silver nanoparticle coupled to an extended silver film have been fully optimized for single molecule Surface-Enhanced Raman Scattering (SERS) spectroscopy. The SERS signal was found to be strongly dependent on the particle size and the molecule orientation with respect to the field inside the nano-gap. Using Finite Difference Time Domain (FDTD) simulations to complement the experimental measurements, the complex interplay between the excitation enhancement and the emission enhancement of the system as a function of particle size were highlighted. Additionally, in conjunction with Density Functional Theory (DFT), the well-defined field direction in the nano-gap enables to recover the orientation of individual molecules.