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.

Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial.

BACKGROUND: Arthroscopic sub-acromial decompression (decompressing the sub-acromial space by removing bone spurs and soft tissue arthroscopically) is a common surgery for subacromial shoulder pain, but its effectiveness is uncertain. We did a study to assess its effectiveness and to investigate the mechanism for surgical decompression. METHODS: We did a multicentre, randomised, pragmatic, parallel group, placebo-controlled, three-group trial at 32 hospitals in the UK with 51 surgeons. Participants were patients who had subacromial pain for at least 3 months with intact rotator cuff tendons, were eligible for arthroscopic surgery, and had previously completed a non-operative management programme that included exercise therapy and at least one steroid injection. Exclusion criteria included a full-thickness torn rotator cuff. We randomly assigned participants (1:1:1) to arthroscopic subacromial decompression, investigational arthroscopy only, or no treatment (attendance of one reassessment appointment with a specialist shoulder clinician 3 months after study entry, but no intervention). Arthroscopy only was a placebo as the essential surgical element (bone and soft tissue removal) was omitted. We did the randomisation with a computer-generated minimisation system. In the surgical intervention groups, patients were not told which type of surgery they were receiving (to ensure masking). Patients were followed up at 6 months and 1 year after randomisation; surgeons coordinated their waiting lists to schedule surgeries as close as possible to randomisation. The primary outcome was the Oxford Shoulder Score (0 [worst] to 48 [best]) at 6 months, analysed by intention to treat. The sample size calculation was based upon a target difference of 4·5 points (SD 9·0). This trial has been registered at ClinicalTrials.gov, number NCT01623011. FINDINGS: Between Sept 14, 2012, and June 16, 2015, we randomly assigned 313 patients to treatment groups (106 to decompression surgery, 103 to arthroscopy only, and 104 to no treatment). 24 [23%], 43 [42%], and 12 [12%] of the decompression, arthroscopy only, and no treatment groups, respectively, did not receive their assigned treatment by 6 months. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression mean 32·7 points [SD 11·6] vs arthroscopy mean 34·2 points [9·2]; mean difference -1·3 points (95% CI -3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], mean difference vs decompression 2·8 points [95% CI 0·5-5·2], p=0·0186; mean difference vs arthroscopy 4·2 [1·8-6·6], p=0·0014) but these differences were not clinically important. There were six study-related complications that were all frozen shoulders (in two patients in each group). INTERPRETATION: Surgical groups had better outcomes for shoulder pain and function compared with no treatment but this difference was not clinically important. Additionally, surgical decompression appeared to offer no extra benefit over arthroscopy only. The difference between the surgical groups and no treatment might be the result of, for instance, a placebo effect or postoperative physiotherapy. The findings question the value of this operation for these indications, and this should be communicated to patients during the shared treatment decision-making process. FUNDING: Arthritis Research UK, the National Institute for Health Research Biomedical Research Centre, and the Royal College of Surgeons (England).

Chlorhexidine bathing and Clostridium difficile infection in a surgical intensive care unit.

BACKGROUND: Clostridium difficile is the most common causative pathogen for hospital-acquired infections in the intensive care unit. This study evaluated the effect of chlorhexidine bathing every other day in preventing hospital-acquired C. difficile infection (CDI) using data from the CHlorhexidine Gluconate BATHing (CHG-BATH) randomized trial. METHODS: The primary endpoint was the proportion of patients acquiring CDIs among patients at risk for incident CDIs. Infections detected >48 h after randomization were classified as incident CDIs. Infections detected before or within 48 h of randomization were classified as prevalent CDIs. RESULTS: Of 38 patients (11.7%) who met criteria for potential CDI and underwent adjudication, 24 (7.4%) received oral or enema vancomycin, 18 (5.5%) had a positive C. difficile molecular assay, 14 (4.3%) received an International Classification of Diseases, Ninth Revision, Clinical Modification code for CDI, and 2 (0.6%) had possible pseudomembranous colitis on histopathology reports. The prevalence of CDI was 3.7% (6 of 164) in the soap and water arm and 4.3% (7 of 161) in the chlorhexidine arm. Compared with daily soap and water bathing, 2% chlorhexidine bathing every other day was not associated with the prevention of hospital-acquired CDI (1.3% [2 of 152] soap and water versus 2.0% [3 of 148] chlorhexidine, P = 0.68). CONCLUSIONS: It is inconclusive if there was an association between chlorhexidine bathing and incidence of CDI among surgical intensive care unit patients in this study as statistical power was limited. There are limited published data evaluating the association between chlorhexidine bathing and CDI, and this study provides data for future systematic reviews and meta-analyses.

Trends in laparoscopic colorectal surgery over time from 2005-2014 using the NSQIP database.

BACKGROUND: Laparoscopy, originally pioneered by gynecologists, was first adopted by general surgeons in the late 1980s. Since then, laparoscopy has been adopted in the surgical specialties and colorectal surgery for treatment of benign and malignant disease. Formal laparoscopic training became a required component of surgery residency programs as validated by the Fundamentals of Laparoscopic Surgery curriculum; however, some surgeons may be more apprehensive of widespread adoption of minimally invasive techniques. Although an overall increase in the use of laparoscopy in colorectal surgery is anticipated over a 10-year period, it is unknown if a similar increase will be seen in higher risk or more acutely ill patients. METHODS: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database from 2005-2014, colorectal procedures were identified by Current Procedural Terminology codes and categorized to open or laparoscopic surgery. The proportion of colorectal surgeries performed laparoscopically was calculated for each year. Separate descriptive statistics was performed and categorized by age and body mass index (BMI). American Society of Anesthesiology (ASA) classification and emergency case status variables were added to the project to help assess complexity of cases. RESULTS: During the 10-year study period, the number of colorectal cases increased from 3114 in 2005 to 51,611 in 2014 as more hospitals joined NSQIP. A total of 277,376 colorectal cases were identified; of which, 114,359 (41.2%) were performed laparoscopically. The use of laparoscopy gradually increased each year, from 22.7% in 2005 to 49.8% in 2014. Laparoscopic procedures were most commonly performed in the youngest age group (18-49 years), overweight and obese patients (BMI 25-34.9), and in ASA class 1-2 patients. Over the 10-year period, there was a noted increase in the use of laparoscopy in every age, BMI, and ASA category, except ASA 5. The percent of emergency cases receiving laparoscopic surgery also doubled from 5.5% in 2005 to 11.5% in 2014. CONCLUSIONS: Over a 10-year period, there was a gradual increase in the use of laparoscopy in colorectal surgery. Further, there was a consistent increase of laparoscopic surgery in all age groups, including the elderly, in all BMI classes, including the obese and morbidly obese, and in most ASA classes, including ASA 3-4, as well as in emergency surgeries. These trends suggest that minimally invasive colorectal surgery appears to be widely adopted and performed on more complex or higher risk patients.

Cross-linking of porcine acellular dermal matrices negatively affects induced neovessel formation using platelet-rich plasma in a rat model of hernia repair.

The degree of cross-linking within acellular dermal matrices (ADM) seems to correlate to neovascularization when used in ventral hernia repair (VHR). Platelet-rich plasma (PRP) enhances wound healing through several mechanisms including neovascularization, but research regarding its effect on soft tissue healing in VHR is lacking. We sought to study the effect of cross-linking on PRP-induced neovascularization in a rodent model of bridging VHR. We hypothesized that ADM cross-linking would negatively affect PRP-induced neovessel formation. PRP was extracted and characterized from pooled whole blood. Porcine cross-linked (cADM) and non-cross-linked ADMs (ncADM) were implanted in a rat model of chronic VHR after treatment with saline (control) or PRP. Neovascularization of samples at 2, 4, and 6 weeks was assessed by hematoxylin and eosin and immunohistochemical staining of CD 31. Adhesion severity at necropsy was compared using a previously validated scale. Addition of PRP increased neovascularization in both cADM and ncADM at 2- and 4-week time points but appeared to do so in a dependent fashion, with significantly greater neovascularization in the PRP-treated ncADMs compared to cADMs. Omental adhesions were increased in all PRP-treated groups. Results indicate that, for 2-week measurements when compared with the cADM group without PRP therapy, the mean change in neovascularization due to ncADM was 3.27 (Z = 2.75, p = 0.006), PRP was 17.56 (Z = 14.77, p < 0.001), and the combined effect of ncADM and PRP was 9.41 (Z = 5.6, p < 0.001). The 4-week data indicate that the average neovascularization change due to ncADM was 0.676 (Z = 0.7, p = 0.484), PRP was 7.69 (Z = 7.95, p < 0.001), and combined effect of ncADM and PRP was 5.28 (Z = 3.86, p < 0.001). These findings validate PRP as a clinical adjunct to enhance the native tissue response to implantable biomaterials and suggest that ncADM is more amenable than cADM to induced neovascularization. PRP use could be advantageous in patients undergoing VHR where poor incorporation is anticipated and early-enhanced neovascularization is desired.

Serum undercarboxylated osteocalcin correlates with hemoglobin A1c in children with recently diagnosed pediatric diabetes.

BACKGROUND: Osteocalcin (OC), a hormone secreted by osteoblasts, improves beta-cell function in vitro and in vivo. We aimed to understand the relationship between OC and hemoglobin A1c (HbA1c) in pediatric diabetes. METHODS: Children (n = 70; mean [SD] age = 11.8 years [3.1]; 34.3% non-Hispanic white, 46.3% Hispanic, 14.9% African-American, 4.5% other) newly diagnosed with diabetes (69.1% type 1 diabetes [T1D], 30.9% type 2 diabetes [T2D]) were studied. We collected clinical data at diagnosis and first clinical visit (V1) 9 weeks later (interquartile range [IQR] = 7.9-12.0). Serum undercarboxylated OC (uOC) and carboxylated OC (cOC) were measured 7.0 weeks (IQR 4.3-8.9) after diagnosis. RESULTS: Mean [SD] uOC was 20.3 (19.6) ng/mL, cOC 29.7 [13.7] ng/mL and u/cOC 0.68 [0.81]. uOC, cOC, or u/cOC were not different by gender, race/ethnicity, age, diabetes type, BMI percentile, or random C-peptide, glucose or HbA1c at diagnosis. However, among 61 children with V1 within 4 months of diagnosis, uOC was higher in those with V1 HbA1c < 7.5% (HbA1c < 58 mmol/mol) (uOC=33.1 [22.0]) compared with children with HbA1c ≥ 7.5% (uOC=17.4 [2.3], P = .0004). The difference was larger among patients with T2D (34.6 and 4.7 ng/mL, respectively, P = .0001) than T1D (32.2 and 19.3, P = .0169), and in males (36.1 and 17.4, P = .018) than females (27.6 and 17.3, P = .072). Analysis for u/cOC were similar while there were no differences in cOC. uOC was inversely correlated with HbA1c at V1 (Spearman's rho = -0.29, P = .02). CONCLUSION: Our findings suggest that serum uOC is inversely related to HbA1c shortly after diagnosis of pediatric diabetes. This potentially modifiable factor of glucose metabolism warrants further studies.

Effect of delirium motoric subtypes on administrative documentation of delirium in the surgical intensive care unit.

This study compares the proportions of surgical intensive care unit (ICU) patients with delirium detected using the Confusion Assessment Method for the ICU (CAM-ICU) who received administrative documentation for delirium using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, stratified by delirium motoric subtypes. This retrospective cohort study was conducted at a surgical ICU from 06/2012 to 05/2013. Delirium was assessed twice daily and was defined as having ≥1 positive CAM-ICU rating. Delirious patients were categorized into hyperactive/mixed and hypoactive subtypes using corresponding Richmond Agitation Sedation Scales. Administrative documentation of delirium was defined as having ≥1 of 32 unique ICD-9-CM codes. Proportions were compared using Pearson's Chi-square test. Of included patients, 40 % (423/1055) were diagnosed with delirium, and 17 % (183/1055) had an ICD-9-CM code for delirium. The sensitivity and specificity of ICD-9-CM codes for delirium were 36 and 95 %. ICD-9-CM codes for delirium were available for 42 % (95 % CI 35-48 %; 105/253) of patients with hyperactive/mixed delirium and 27 % (95 % CI 20-34 %; 46/170) of patients with hypoactive delirium (relative risk = 1.5; 95 % CI 1.2-2.0; p = 0.002). ICD-9-CM codes yielded a low sensitivity for identifying patients with CAM-ICU positive delirium and were more likely to identify hyperactive/mixed delirium compared with hypoactive delirium.

Effect of Chlorhexidine Bathing Every Other Day on Prevention of Hospital-Acquired Infections in the Surgical ICU: A Single-Center, Randomized Controlled Trial.

OBJECTIVE: To test the hypothesis that compared with daily soap and water bathing, 2% chlorhexidine gluconate bathing every other day for up to 28 days decreases the risk of hospital-acquired catheter-associated urinary tract infection, ventilator-associated pneumonia, incisional surgical site infection, and primary bloodstream infection in surgical ICU patients. DESIGN: This was a single-center, pragmatic, randomized trial. Patients and clinicians were aware of treatment-group assignment; investigators who determined outcomes were blinded. SETTING: Twenty-four-bed surgical ICU at a quaternary academic medical center. PATIENTS: Adults admitted to the surgical ICU from July 2012 to May 2013 with an anticipated surgical ICU stay for 48 hours or more were included. INTERVENTIONS: Patients were randomized to bathing with 2% chlorhexidine every other day alternating with soap and water every other day (treatment arm) or to bathing with soap and water daily (control arm). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was a composite outcome of catheter-associated urinary tract infection, ventilator-associated pneumonia, incisional surgical site infection, and primary bloodstream infection. Of 350 patients randomized, 24 were excluded due to prior enrollment in this trial and one withdrew consent. Therefore, 325 were analyzed (164 soap and water versus 161 chlorhexidine). Patients acquired 53 infections. Compared with soap and water bathing, chlorhexidine bathing every other day decreased the risk of acquiring infections (hazard ratio = 0.555; 95% CI, 0.309-0.997; p = 0.049). For patients bathed with soap and water versus chlorhexidine, counts of incident hospital-acquired infections were 14 versus 7 for catheter-associated urinary tract infection, 13 versus 8 for ventilator-associated pneumonia, 6 versus 3 for incisional surgical site infections, and 2 versus 0 for primary bloodstream infection; the effect was consistent across all infections. The absolute risk reduction for acquiring a hospital-acquired infection was 9.0% (95% CI, 1.5-16.4%; p = 0.019). Incidences of adverse skin occurrences were similar (18.9% soap and water vs 18.6% chlorhexidine; p = 0.95). CONCLUSIONS: Compared with soap and water, chlorhexidine bathing every other day decreased the risk of acquiring infections by 44.5% in surgical ICU patients.

Outcomes and Resource Use of Sepsis-associated Stays by Presence on Admission, Severity, and Hospital Type.

OBJECTIVE: To establish a baseline for the incidence of sepsis by severity and presence on admission in acute care hospital settings before implementation of a broad sepsis screening and response initiative. METHODS: A retrospective cohort study using hospital discharge abstracts of 5672 patients, aged 18 years and above, with sepsis-associated stays between February 2012 and January 2013 at an academic medical center and 5 community hospitals in Texas. RESULTS: Sepsis was present on admission in almost 85% of cases and acquired in-hospital in the remainder. The overall inpatient death rate was 17.2%, but was higher in hospital-acquired sepsis (38.6%, medical; 29.2%, surgical) and Stages 2 (17.6%) and 3 (36.4%) compared with Stage 1 (5.9%). Patients treated at the academic medical center had a higher death rate (22.5% vs. 15.1%, P<0.001) and were more costly ($68,050±184,541 vs. $19,498±31,506, P<0.001) versus community hospitals. CONCLUSIONS: Greater emphasis is needed on public awareness of sepsis and the detection of sepsis in the prehospitalization and early hospitalization period. Hospital characteristics and case mix should be accounted for in cross-hospital comparisons of sepsis outcomes and costs.

The nanochannel delivery system for constant testosterone replacement therapy.

INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.

Reductions in Sepsis Mortality and Costs After Design and Implementation of a Nurse-Based Early Recognition and Response Program.

BACKGROUND: Sepsis is a leading cause of death, but evidence suggests that early recognition and prompt intervention can save lives. In 2005 Houston Methodist Hospital prioritized sepsis detection and management in its ICU. In late 2007, because of marginal effects on sepsis death rates, the focus shifted to designing a program that would be readily used by nurses and ensure early recognition of patients showing signs suspicious for sepsis, as well as the institution of prompt, evidence-based interventions to diagnose and treat it. METHODS: The intervention had four components: organizational commitment and data-based leadership; development and integration of an early sepsis screening tool into the electronic health record; creation of screening and response protocols; and education and training of nurses. Twice-daily screening of patients on targeted units was conducted by bedside nurses; nurse practitioners initiated definitive treatment as indicated. Evaluation focused on extent of implementation, trends in inpatient mortality, and, for Medicare beneficiaries, a before-after (2008-2011) comparison of outcomes and costs. A federal grant in 2012 enabled expansion of the program. RESULTS: By year 3 (2011) 33% of inpatients were screened (56,190 screens in 9,718 unique patients), up from 10% in year 1 (2009). Inpatient sepsis-associated death rates decreased from 29.7% in the preimplementation period (2006-2008) to 21.1% after implementation (2009-2014). Death rates and hospital costs for Medicare beneficiaries decreased from preimplementation levels without a compensatory increase in discharges to postacute care. CONCLUSION: This program has been associated with lower inpatient death rates and costs. Further testing of the robustness and exportability of the program is under way.

Comparison of cognitive behaviour therapy versus activity management, both delivered remotely, to treat paediatric chronic fatigue syndrome/myalgic encephalomyelitis: the UK FITNET-NHS RCT.

Design: Parallel-group randomised controlled trial. Methods: Adolescents aged 11-17 years, diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome and with no local specialist treatment centre, were referred to a specialist service in South West England. Interventions: Fatigue In Teenagers on the interNET in the National Health Service is a web-based myalgic encephalomyelitis/chronic fatigue syndrome-focused cognitive-behavioural therapy programme for adolescents, supported by individualised written, asynchronous electronic consultations with a clinical psychologist/cognitive-behavioural therapy practitioner. The comparator was videocall-delivered activity management with a myalgic encephalomyelitis/chronic fatigue syndrome clinician. Both treatments were intended to last 6 months. Objectives: Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for paediatric myalgic encephalomyelitis/chronic fatigue syndrome. Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for those with mild/moderate comorbid mood disorders. From a National Health Service perspective, estimate the cost-effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management over a 12-month horizon. Primary Outcome: 36-item Short Form Health Survey Physical Function subscale at 6 months post randomisation. Randomisation: Web-based, using minimisation with a random component to balance allocated groups by age and gender. Blinding: While the investigators were blinded to group assignment, this was not possible for participants, parents/carers and therapists. Results: The treatment of 314 adolescents was randomly allocated, 155 to Fatigue In Teenagers on the interNET in the National Health Service. Mean age was 14 years old and 63% were female. Primary outcome: At 6 months, participants allocated to Fatigue In Teenagers on the interNET in the National Health Service were more likely to have improved physical function (mean 60.5, standard deviation 29.5, n = 127) compared to Activity Management (mean 50.3, standard deviation 26.5, n = 138). The mean difference was 8.2 (95% confidence interval 2.7 to 13.6, p = 0.003). The result was similar for participants meeting the National Institute for Health and Care Excellence 2021 diagnostic criteria. Secondary outcomes: Fatigue In Teenagers on the interNET in the National Health Service participants attended, on average, half a day more school per week at 6 months than those allocated Activity Management, and this difference was maintained at 12 months. There was no strong evidence that comorbid mood disorder impacted upon the relative effectiveness of the two interventions. Similar improvement was seen in the two groups for pain and the Clinical Global Impression scale, with a mixed picture for fatigue. Both groups continued to improve, and no clear difference in physical function remained at 12 months [difference in means 4.4 (95% confidence interval -1.7 to 10.5)]. One or more of the pre-defined measures of a worsening condition in participants during treatment, combining therapist and patient reports, were met by 39 (25%) participants in the Fatigue In Teenagers on the interNET in the National Health Service group and 42 (26%) participants in the Activity Management group. A small gain was observed for the Fatigue In Teenagers on the interNET in the National Health Service group compared to Activity Management in quality-adjusted life-years (0.002, 95% confidence interval -0.041 to 0.045). From an National Health Service perspective, the costs were £1047.51 greater in the Fatigue In Teenagers on the interNET in the National Health Service group (95% confidence interval £624.61 to £1470.41). At a base cost-effectiveness threshold of £20,000 per quality-adjusted life-year, the incremental cost-effectiveness ratio was £457,721 with incremental net benefit of -£1001 (95% confidence interval -£2041 to £38). Conclusion: At 6 months post randomisation, compared with Activity Management, Fatigue In Teenagers on the interNET in the National Health Service improved physical function and school attendance. The additional cost of Fatigue In Teenagers on the interNET in the National Health Service and limited sustained impact mean it is unlikely to be cost-effective. Trial registration: This trial is registered as ISRCTN18020851. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/109) and is published in full in Health Technology Assessment; Vol. 28, No. 70. See the NIHR Funding and Awards website for further award information.

Why did we do the study? The best evidence for the treatment of adolescents with myalgic encephalomyelitis/chronic fatigue syndrome is cognitive­behavioural therapy for fatigue delivered in person. In the United Kingdom, most adolescents with myalgic encephalomyelitis/chronic fatigue syndrome cannot get this specialist treatment where they live. Fatigue In Teenagers on the interNET in the National Health Service is an online treatment using cognitive­behavioural therapy designed for myalgic encephalomyelitis/chronic fatigue syndrome, which has been shown to work in the Netherlands. To find out if Fatigue In Teenagers on the interNET in the National Health Service would be beneficial in the United Kingdom, we compared Fatigue In Teenagers on the interNET in the National Health Service to Activity Management. Activity Management is the treatment most often offered to children and young people with myalgic encephalomyelitis/chronic fatigue syndrome in the United Kingdom, and aims to avoid peaks in activity (sometimes called 'pacing'). What was the question? Does Fatigue In Teenagers on the interNET in the National Health Service lead to greater improvements in children and young people with myalgic encephalomyelitis/chronic fatigue syndrome when compared to Activity Management, when both interventions are delivered remotely? What did we do? We compared Fatigue In Teenagers on the interNET in the National Health Service and Activity Management in two comparable groups of children, and measured physical function at 6 months as the main indication of improvement. We measured how much the treatments cost and we asked children and young people, their parents and treatment providers what they thought about the two interventions. What did we find? At 6 months, adolescents saw greater improvements in physical function, and attended half a day more school per week, with Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management. Both interventions were associated with improvements over 12 months, with there being no clear difference between them after that time. However, the Fatigue In Teenagers on the interNET in the National Health Service treatment was more expensive. What does this mean? We have shown that cognitive­behavioural therapy for fatigue can be provided online to children as Fatigue In Teenagers on the interNET in the National Health Service, leading to faster improvement in physical function and greater school attendance compared to Activity Management. However, Fatigue In Teenagers on the interNET in the National Health Service is expensive and is unlikely to be good value for money.

Comparison of surgical or non-surgical management for non-acute anterior cruciate ligament injury: the ACL SNNAP RCT.

Background: Anterior cruciate ligament injury of the knee is common and leads to decreased activity and risk of secondary osteoarthritis of the knee. Management of patients with a non-acute anterior cruciate ligament injury can be non-surgical (rehabilitation) or surgical (reconstruction). However, insufficient evidence exists to guide treatment. Objective(s): To determine in patients with non-acute anterior cruciate ligament injury and symptoms of instability whether a strategy of surgical management (reconstruction) without prior rehabilitation was more clinically and cost-effective than non-surgical management (rehabilitation). Design: A pragmatic, multicentre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Due to the nature of the interventions, no blinding could be carried out. Setting: Twenty-nine NHS orthopaedic units in the United Kingdom. Participants: Participants with a symptomatic (instability) non-acute anterior cruciate ligament-injured knee. Interventions: Patients in the surgical management arm underwent surgical anterior cruciate ligament reconstruction as soon as possible and without any further rehabilitation. Patients in the rehabilitation arm attended physiotherapy sessions and only were listed for reconstructive surgery on continued instability following rehabilitation. Surgery following initial rehabilitation was an expected outcome for many patients and within protocol. Main outcome measures: The primary outcome was the Knee Injury and Osteoarthritis Outcome Score 4 at 18 months post randomisation. Secondary outcomes included 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. Results: Three hundred and sixteen participants were recruited between February 2017 and April 2020 with 156 randomised to surgical management and 160 to rehabilitation. Forty-one per cent (n = 65) of those allocated to rehabilitation underwent subsequent reconstruction within 18 months with 38% (n = 61) completing rehabilitation and not undergoing surgery. Seventy-two per cent (n = 113) of those allocated to surgery underwent reconstruction within 18 months. Follow-up at the primary outcome time point was 78% (n = 248; surgical, n = 128; rehabilitation, n = 120). Both groups improved over time. Adjusted mean Knee Injury and Osteoarthritis Outcome Score 4 scores at 18 months had increased to 73.0 in the surgical arm and to 64.6 in the rehabilitation arm. The adjusted mean difference was 7.9 (95% confidence interval 2.5 to 13.2; p = 0.005) in favour of surgical management. The per-protocol analyses supported the intention-to-treat results, with all treatment effects favouring surgical management at a level reaching statistical significance. There was a significant difference in Tegner Activity Score at 18 months. Sixty-eight per cent (n = 65) of surgery patients did not reach their expected activity level compared to 73% (n = 63) in the rehabilitation arm. There were no differences between groups in surgical complications (n = 1 surgery, n = 2 rehab) or clinical events (n = 11 surgery, n = 12 rehab). Of surgery patients, 82.9% were satisfied compared to 68.1% of rehabilitation patients. Health economic analysis found that surgical management led to improved health-related quality of life compared to non-surgical management (0.052 quality-adjusted life-years, p = 0.177), but with higher NHS healthcare costs (£1107, p < 0.001). The incremental cost-effectiveness ratio for the surgical management programme versus rehabilitation was £19,346 per quality-adjusted life-year gained. Using £20,000-30,000 per quality-adjusted life-year thresholds, surgical management is cost-effective in the UK setting with a probability of being the most cost-effective option at 51% and 72%, respectively. Limitations: Not all surgical patients underwent reconstruction, but this did not affect trial interpretation. The adherence to physiotherapy was patchy, but the trial was designed as pragmatic. Conclusions: Surgical management (reconstruction) for non-acute anterior cruciate ligament-injured patients was superior to non-surgical management (rehabilitation). Although physiotherapy can still provide benefit, later-presenting non-acute anterior cruciate ligament-injured patients benefit more from surgical reconstruction without delaying for a prior period of rehabilitation. Future work: Confirmatory studies and those to explore the influence of fidelity and compliance will be useful. Trial registration: This trial is registered as Current Controlled Trials ISRCTN10110685; ClinicalTrials.gov Identifier: NCT02980367. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/140/63) and is published in full in Health Technology Assessment; Vol. 28, No. 27. See the NIHR Funding and Awards website for further award information.

The study aimed to find out whether it is better to offer surgical reconstruction or rehabilitation first to patients with a more long-standing injury of their anterior cruciate ligament in their knee. This injury causes physical giving way of the knee and/or sensations of it being wobbly (instability). The instability can affect daily activities, work, sport and can lead to arthritis. There are two main treatment options for this problem: non-surgical rehabilitation (prescribed exercises and advice from physiotherapists) or an operation by a surgeon to replace the damaged ligament (anterior cruciate ligament reconstruction). Although studies have highlighted the best option for a recently injured knee, the best management was not known for patients with a long-standing injury, perhaps occurring several months previously. Because the surgery is expensive to the NHS (around £100 million per year), it was also important to look at the costs involved. We carried out a study recruiting 316 non-acute anterior cruciate ligament-injured patients from 29 different hospitals and allocated each patient to either surgery or rehabilitation as their treatment option. We measured how well they did with special function and activity scores, patient satisfaction and costs of treatment. Patients in both groups improved substantially. It was expected that some patients in the rehabilitation group would want surgery if non-surgical management was unsuccessful. Forty-one per cent of patients who initially underwent rehabilitation subsequently elected to have reconstructive surgery. Overall, the patients allocated to the surgical reconstruction group had better results in terms of knee function and stability, activity level and satisfaction with treatment than patients allocated to the non-operative rehabilitation group. There were few problems or complications with either treatment option. Although the surgery was a more expensive treatment option, it was found to be cost-effective in the UK setting. The evidence can be discussed in shared decision-making with anterior cruciate ligament-injured patients. Both strategies of management led to improvement. Although a rehabilitation strategy can be beneficial, especially for recently injured patients, it is advised that later-presenting non-acute and more long-standing anterior cruciate ligament-injured patients undergo surgical reconstruction without necessarily delaying for a period of rehabilitation.

The effectiveness and cost-effectiveness of a group domestic abuse perpetrator programme: protocol for a randomised controlled trial.

BACKGROUND: In contrast to evidence for interventions supporting victim/survivors of domestic violence and abuse (DVA), the effectiveness of perpetrator programmes for reduction of abuse is uncertain. This study aims to estimate the effectiveness and cost-effectiveness of a perpetrator programme for men. METHODS: Pragmatic two-group individually randomised controlled trial (RCT) with embedded process and economic evaluation. Five centres in southwest England and South Wales aim to recruit 316 (reduced from original target of 366) male domestic abuse perpetrators. These will be randomised 2:1 to a community-based domestic abuse perpetrator programme (DAPP) or usual care comparator with 12-month follow-up. Female partners/ex-partners will be invited to join the study. The intervention for men comprises 23 weekly sessions of a group programme delivered in voluntary sector domestic abuse services. The intervention for female partners/ex-partners is one-to-one support from a safety worker. Men allocated to usual care receive no intervention; however, they are free to access other services. Their partners/ex-partners will be signposted to support services. Data is collected at baseline, and 4, 8 and 12 months' follow-up. The primary outcome is men's self-reported abusive behaviour measured by the Abusive Behaviour Inventory (ABI-29) at 12 months. Secondary measures include physical and mental health status and resource use alongside the abuse measure ABI (ABI-R) for partners/ex-partners and criminal justice contact for men. A mixed methods process evaluation and qualitative study will explore mechanisms of effectiveness, judge fidelity to the intervention model using interviews and group observations. The economic evaluation, over a 1-year time horizon from three perspectives (health and social care, public sector and society), will employ a cost-consequences framework reporting costs alongside economic outcomes (Quality-Adjusted Life Years derived from EQ-5D-5L, SF-12 and CHU-9D, and ICECAP-A) as well as the primary and other secondary outcomes. DISCUSSION: This trial will provide evidence of the (cost)effectiveness of a DAPP. The embedded process evaluation will further insights in the experiences and contexts of participants and their journey through a perpetrator programme, and the study will seek to address the omission in other studies of economic evaluations. TRIAL REGISTRATION: ISRCTN15804282, April 1, 2019.

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.

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.

Clinical outcomes of pancreaticoduodenectomy in octogenarians: a surgeon's experience from 2007 to 2015.

BACKGROUND: As the number of elderly people in our population increases, there will be a greater number of octogenarians who will need pancreaticoduodenectomy as the only curative option for periampullary malignancies. This study evaluated clinical outcomes of pancreaticoduodenectomy in octogenarians, in comparison to younger patients. METHODS: A retrospective review was conducted of 216 consecutive patients who underwent pancreaticoduodenectomy from January 2007 to April 2015. A two-sided Fisher's exact statistical analysis was used to compare pre-operative comorbidities, intra-operative factors, surgical pathology, and post-operative complication rates between non-octogenarians and octogenarians. RESULTS: One hundred and eighty three non-octogenarians and 33 octogenarians underwent pancreaticoduodenectomy. Of patients with periampullary adenocarcinoma, octogenarians were more likely to present with advanced disease state (P=0.01). The two cohorts had similar ASA scores (P=0.62); however, octogenarians were more likely to have coronary artery disease (P=0.03). The length of operation was shorter in octogenarians (P=0.002). Mortality rates (P=0.49) and overall postoperative complication rates (P=1.0) were similar in two cohorts; however octogenarians had a higher incidence of pulmonary embolism (P=0.02). CONCLUSIONS: Our data demonstrates that octogenarians can undergo pancreaticoduodenectomy with outcomes similar to those in younger patients. Thus, patients should not be denied a curative surgical option for periampullary malignancy based on advanced age alone.

Surgeon-Specific Reports in General Surgery: Establishing Benchmarks for Peer Comparison Within a Single Hospital.

BACKGROUND: Methods to assess a surgeon's individual performance based on clinically meaningful outcomes have not been fully developed, due to small numbers of adverse outcomes and wide variation in case volumes. The Achievable Benchmark of Care (ABC) method addresses these issues by identifying benchmark-setting surgeons with high levels of performance and greater case volumes. This method was used to help surgeons compare their surgical practice to that of their peers by using merged National Surgical Quality Improvement Program (NSQIP) and Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) data to generate surgeon-specific reports. STUDY DESIGN: A retrospective cohort study at a single institution's department of surgery was conducted involving 107 surgeons (8,660 cases) over 5.5 years. Stratification of more than 32,000 CPT codes into 16 CPT clusters served as the risk adjustment. Thirty-day outcomes of interest included surgical site infection (SSI), acute kidney injury (AKI), and mortality. Performance characteristics of the ABC method were explored by examining how many surgeons were identified as benchmark-setters in view of volume and outcome rates within CPT clusters. RESULTS: For the data captured, most surgeons performed cases spanning a median of 5 CPT clusters (range 1 to 15 clusters), with a median of 26 cases (range 1 to 776 cases) and a median of 2.8 years (range 0 to 5.5 years). The highest volume surgeon for that CPT cluster set the benchmark for 6 of 16 CPT clusters for SSIs, 8 of 16 CPT clusters for AKIs, and 9 of 16 CPT clusters for mortality. CONCLUSIONS: The ABC method appears to be a sound and useful approach to identifying benchmark-setting surgeons within a single institution. Such surgeons may be able to help their peers improve their performance.

Mapping Radiation Injury and Recovery in Bone Marrow Using 18F-FLT PET/CT and USPIO MRI in a Rat Model.

UNLABELLED: We present and test the use of multimodality imaging as a topological tool to map the amount of the body exposed to ionizing radiation and the location of exposure, which are important indicators of survival and recovery. To achieve our goal, PET/CT imaging with 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was used to measure cellular proliferation in bone marrow (BM), whereas MRI using ultra-small superparamagnetic iron oxide (USPIO) particles provided noninvasive information on radiation-induced vascular damage. METHODS: Animals were x-ray-irradiated at a dose of 7.5 Gy with 1 of 3 radiation schemes-whole-body irradiation, half-body shielding (HBS), or 1-leg shielding (1LS)-and imaged repeatedly. The spatial information from the CT scan was used to segment the region corresponding to BM from the PET scan using algorithms developed in-house, allowing for quantification of proliferating cells, and BM blood volume was estimated by measuring the changes in the T2 relaxation rates (ΔR2) collected from MR scans. RESULTS: (18)F-FLT PET/CT imaging differentiated irradiated from unirradiated BM regions. Two days after irradiation, proliferation of 1LS animals was significantly lower than sham (P = 0.0001, femurs; P < 0.0001, tibias) and returned to sham levels by day 10 (P = 0.6344, femurs; P = 0.3962, tibias). The degree of shielding affected proliferation recovery, showing an increase in the irradiated BM of the femurs, but not the tibias, of HBS animals when compared with 1LS (P = 0.0310, femurs; P = 0.5832, tibias). MRI of irradiated spines detected radiation-induced BM vascular damage, measured by the significant increase in ΔR2 2 d after whole-body irradiation (P = 0.0022) and HBS (P = 0.0003) with a decreasing trend of values, returning to levels close to baseline over 10 d. Our data were corroborated using γ-counting and histopathology. CONCLUSION: We demonstrated that (18)F-FLT PET/CT and USPIO MRI are valuable tools in mapping regional radiation exposure and the effects of radiation on BM. Analysis of the (18)F-FLT signal allowed for a clear demarcation of exposed BM regions and elucidated the kinetics of BM recovery, whereas USPIO MRI was used to assess vascular damage and recovery.