129Xe MRI Ventilation Textures and Longitudinal Quality-of-Life Improvements in Long-COVID.

RATIONALE AND OBJECTIVES: It remains difficult to predict longitudinal outcomes in long-COVID, even with chest CT and functional MRI. 129Xe MRI reflects airway dysfunction, measured using ventilation defect percent (VDP) and in long-COVID patients, MRI VDP was abnormal, suggestive of airways disease. While MRI VDP and quality-of-life improved 15-month post-COVID infection, both remained abnormal. To better understand the relationship of airways disease and quality-of-life improvements in patients with long-COVID, we extracted 129Xe ventilation MRI textures and generated machine-learning models in an effort to predict improved quality-of-life, 15-month post-infection. MATERIALS AND METHODS: Long-COVID patients provided written-informed consent to 3-month and 15-month post-infection visits. Pyradiomics was used to extract 129Xe ventilation MRI texture features, which were ranked using a Random-Forest classifier. Top-ranking features were used in classification models to dichotomize patients based on St. George's Respiratory Questionnaire (SGRQ) score improvement greater than the minimal-clinically-important-difference (MCID). Classification performance was evaluated using the area under the receiver-operator-characteristic-curve (AUC), sensitivity, and specificity. RESULTS: 120 texture features were extracted from 129Xe ventilation MRI in 44 long-COVID participants (54 ± 14 years), including 30 (52 ± 12 years) with ΔSGRQ≥MCID and 14 (58 ± 18 years) with ΔSGRQ

Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.

Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.

Applying the lessons of design thinking: a unique programme of care for acutely unwell, community-dwelling COVID-19 patients.

BACKGROUND: The COVID-19 pandemic limited access to primary care and in-person assessments requiring healthcare providers to re-envision care delivery for acutely unwell outpatients. Design thinking methodology has the potential to support the robust evolution of a new clinical model. AIM: To demonstrate how design thinking methodology can rapidly and rigorously create and evolve a safe, timely, equitable and patient-centred programme of care, and to share valuable lessons for effective implementation of design thinking solutions to address complex problems. METHOD: We describe how design thinking methodology was employed to create a new clinical model of care. Using the example of a novel telemedicine programme to support acutely unwell, community-dwelling COVID-19-positive patients called the London Urgent COVID-19 Care Clinic (LUC3), we show how continuous quality outcomes (safety, timeliness, equity and patient-centredness), as well as patient experience survey responses, can drive iterative changes in programme delivery. RESULTS: The inspiration phase identified four key needs for this patient population: monitoring COVID-19 signs and symptoms; self-managing COVID-19 symptoms; managing other comorbidities in the setting of COVID-19; and escalating care as needed. Guided by these needs, a cross-disciplinary stakeholder group was engaged in the ideation and implementation phases to create a unique and comprehensive telemedicine programme (LUC3). During the implementation phase, LUC3 assessed 2202 community-based patients diagnosed with acute COVID-19; the collected quality outcomes and end-user feedback led to evolution of programme delivery. CONCLUSION: Design thinking methodology provided an essential framework and valuable lessons for the development of a safe, equitable, timely and patient-centred telemedicine care programme. The lessons learnt here-the importance of inclusive collaboration, using empathy to guide equity-focused interventions, leveraging continuous metrics to drive iteration and aiming for good-if-not-perfect plans-can serve as a road map for using design thinking for targeted healthcare problems.

J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine.

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

Adolescent displaced lateral-end clavicle fractures are not comparable to the adult variant. Epidemiology, fracture patterns and outcome of non-operative management.

Background: The primary aim of this study was to determine the epidemiology of lateral-end clavicle fractures in adolescents. The secondary aim was to assess the outcome following non-operative management. Methods: A retrospective review of all adolescent clavicle fractures over a 10-year period was undertaken. Fracture classification, demographics, management, and complications were analysed. Functional outcomes were undertaken with the Quick Disabilities of Arm, Shoulder and Hand and EuroQol five-dimension at mean 8.8 years post-injury. Results: In total, 677 clavicle fractures were analysed, 8.7% were lateral-end fractures (n = 59/677). The median age was 14.6 (range: 13-17) and 92% were male (n = 54/59). The incidence was 0.17 per 100,000 per year. All displaced physeal fractures (Neer IV n = 14) were managed non-operatively and of the six followed-up, all united with good outcomes. The adult type displaced fracture (Neer II) occurred in fifteen fractures, five underwent operative fixation and ten were managed non-operatively with one subsequent nonunion (n = 1/10). Those patients that underwent non-operative management (response n = 5/10, 50%) reported a median Quick Disabilities of Arm, Shoulder and Hand of 2.3 but approximately 40% reported cosmetic and outcome dissatisfaction at long-term follow-up. Conclusion: Displaced Neer II lateral-end clavicle fractures are rare in the adolescent population. Although nonunion is rare, some dissatisfaction with cosmesis persists at long-term follow-up despite good functional outcomes with non-operative management.

Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (ß = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities.

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=-0.7; 95%CI=-0.2 to -1.2, p=0.019), St George's Respiratory Questionnaire-score (SGRQ Δ=-6; 95% CI=-1 to -11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome.

BACKGROUND: Patients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS). METHODS: Consenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only. RESULTS: Seventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03). CONCLUSION: 129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores. TRIAL REGISTRATION NUMBER: NCT05014516.

Hyperpolarized 129Xe Pulmonary MRI and Asymptomatic Atrial Septal Defect.

In an asymptomatic 19-year-old who regularly underwent cardiopulmonary fitness testing for national lifeguard-accreditation, 129Xe MRI unexpectedly revealed an abnormally augmented RBC signal and RBC-to-alveolar-capillary-tissue ratio with spatially homogeneous ventilation, tissue barrier, and RBC images. Pulmonary function was normal, but cardiopulmonary follow-up including transthoracic and transesophageal echocardiogram, heart catheterization, and contrast-enhanced cardiac CT imaging led to the diagnosis of a large (20 × 27 mm) secundum atrial septal defect (ASD) with a net right-to-left shunt (Qp:Qs = 0.5) and normal pulmonary pressures. This novel, unexpected case revealed that 129Xe RBC signal intensity likely reflected erythrocytosis, compensatory to the abnormal cardiovascular hemodynamics that resulted from a large congenital ASD. Unlike ASD cases that present with dyspnea and exercise limitation, this 129Xe MRI abnormality was detected in an asymptomatic teenager. This is the first report of asymptomatic adult congenital heart disease diagnosed subsequent to novel 129Xe MRI that led to early intervention, avoiding long-term complications of cyanosis, including ventricular fibrosis and thromboembolic and bleeding risks.

In Vitro Evaluation of the Stabilization Time of Chemical Bonds During Setting Reaction and Microhardness of Preheated Glass-Ionomer Cements.

OBJECTIVES: To evaluate the effect of preheating glass-ionomer cement (GIC) restorative materials on stabilization time (ST) of their metal carboxylate bonds and on microhardness. METHODS AND MATERIALS: Two conventional high-viscosity GICs, Ketac Universal (3M ESPE) and Equia Forte (GC), were evaluated. The thermographic camera was used to measure the temperature inside the glass-ionomer cement capsules before and after heating. The preheating of capsules was performed at 54°C for 30 seconds in a commercial device. Characterization of ST in the GICs was determined by Fourier Transform Infrared (FTIR) spectroscopy. For this, 10 samples of each material were prepared, five in the non-preheated group (control) and five with preheating. FTIR spectra were obtained 10 minutes after mixing (control group) or after heating and then every 10 minutes for 120 minutes. For the microhardness test, 20 cylindrical specimens (3 mm height x 6 mm diameter) were prepared for each material (10 preheated, 10 control). The microhardness was determined at three time intervals: 10 minutes after mixing, after the ST as detected through the FTIR part of the study, and after one week. Knoop microhardness was assessed using a diamond indenter with a 25 g load and 15 seconds dwell time. RESULTS: Ketac Universal showed an increase in temperatures of 15.7°C for powder and 3.6°C for liquid, while Equia Forte showed 16.4°C for powder and 8.5°C for liquid. FTIR spectra indicated that preheating reduced the ST for Equia Forte but increased it for Ketac Universal. Preheating increased the initial microhardness (T1) of Equia Forte. With maturation over one week, it was observed that preheating significantly improved the microhardness of both materials compared with the control specimens. CONCLUSION: Preheating influenced the ST and the microhardness of Ketac Universal and Equia Forte. The ST and microhardness of Ketac Universal increased after seven days, whereas Equia Forte showed a reduced ST and increased microhardness from the outset.

Fracture nonunion in long bones: A literature review of risk factors and surgical management.

Nonunion following a long bone fracture causes considerable morbidity when it occurs. Risk factors depend on specific fractures but there is a complex interplay of injury severity, comorbidities, patient medication and infection. The majority of nonunions occur after long bone fractures with the tibia, femur, forearm, humerus and clavicle predominating. Despite interest in the biological augmentation of fracture healing, the majority of nonunions can be effectively managed with conventional surgical techniques. In this review we present a review of risk factors for nonunion and the outcome following surgical management.

Monitoring of fracture healing. Update on current and future imaging modalities to predict union.

Fracture nonunion causes considerable patient morbidity and an associated burden to society. Traditional reliance on radiographs to monitor union has limitations as bridging callus of long bone fractures can take three or more months to occur. Computed Tomographic (CT) scanning is becoming increasingly popular and can evaluate bridging callus in the late stages of healing to confirm union. The use of dynamic contrast enhanced Magnetic Resonance Imaging (MRI) and advances in nuclear imaging may yield benefits in the assessment of the infected nonunion. Emerging evidence supports the use of ultrasound to detect bridging callus prior to radiographic confirmation and it may be of use to predict patients at high risk of nonunion. This paper is part of a Supplement supported by The Osteosynthesis and Trauma Care Foundation (OTCF).

Endoscopic Botulinum toxin as a treatment for delayed gastric emptying following oesophagogastrectomy.

INTRODUCTION: The incidence of delayed gastric emptying (DGE) following oesophagogastrectomy with gastric conduit reconstruction is reported to be between 1.7% and 50%. This variation is due to differing practices of intraoperative pylorus drainage procedures, which increase the risk of postoperative biliary reflux and dumping syndrome, resulting in significant morbidity. The aim of our study was to establish rates of DGE in people undergoing oesophagogastrectomy without routine intraoperative drainage procedures, and to evaluate outcomes of postoperative endoscopically administered Botulinum toxin into the pylorus (EBP) for people with DGE resistant to systemic pharmacological treatment. METHODS: All patients undergoing oesophagogastrectomy between 1 January 2016 and 31 March 2018 at our unit were included. No intraoperative pyloric drainage procedures were performed, and DGE resistant to systemic pharmacotherapy was managed with EBP. RESULTS: Ninety-seven patients were included. Postoperatively, 29 patients (30%) were diagnosed with DGE resistant to pharmacotherapy. Of these, 16 (16.5%) were diagnosed within 30 days of surgery. The median pre-procedure nasogastric tube aspirate was 780ml; following EBP, this fell to 125ml (p<0.001). Median delay from surgery to EBP in this cohort was 13 days (IQR 7-16 days). Six patients required a second course of EBP, with 100% successful resolution of DGE before discharge. There were no procedural complications. CONCLUSIONS: This is the largest series of patients without routine intraoperative drainage procedures. Only 30% of patients developed DGE resistant to pharmacotherapy, which was managed safely with EBP in the postoperative period, thus minimising the risk of biliary reflux in people who would otherwise be at risk following prophylactic pylorus drainage procedures.

All-fiber widely tunable ultrafast laser source for multimodal imaging in nonlinear microscopy.

In this Letter, we present an all-fiber, easy-to-use, wavelength-tunable, ultrafast laser, based on soliton self-frequency shifting in an Er-doped polarization-maintaining very large mode area fiber. The system is tunable over 370 nm, starting at 1620 nm, with an average power of up to 1.5 W that emits 120 fs short laser pulses directly out of the fusion-spliced fiber without using bulky pulse compression optics. The output is subsequently frequency doubled to a wavelength range covering 810 nm up to almost 1000 nm with more than 500 mW average power and 120 fs pulse width. Having a polarization extinction ratio better than 40 dB and a M2 of 1.1, the fully computer-controlled laser system presents a robust and compact laser source. These parameters make the laser perfectly suited for multimodal imaging in nonlinear microscopy.

Sonographic bridging callus: An early predictor of fracture union.

BACKGROUND: There is currently a lack of agreed criteria for sonographic assessment of callus and reliability between reviewers. The primary aim of this study was to determine criteria and reviewer agreement for sonographic bridging callus (SBC) on ultrasound. The secondary aim was to analyse the use of ultrasound to detect bridging callus in a prospective cohort of patients with a conservatively managed clavicle fracture. METHODS: A prospective cohort of conservatively managed displaced midshaft clavicle fractures underwent ultrasound scanning at three-, six- and 12-weeks post-injury. The main outcome was nonunion confirmed at six months on CT scanning. Five patients with confirmed nonunion were compared against a control group of 15 patients with timely union at three months. The ultrasound scans were interpreted by two blinded reviewers to evaluate sonographic callus features with agreement determined by weighted kappa. A further validation study was undertaken by four blinded reviewers using the intraclass-correlation-coefficient (ICC) using the most clinically relevant findings of the pilot work. RESULTS: At three weeks post-injury fibrocartilaginous material was present in 80% of patients (16/20). When detected this was associated with union (sensitivity 93%, specificity 60%, p = 0.03) with the inter-observer agreement rated 'fair' on kappa (0.44). At six weeks only 10% (2/20) of patients had bridging callus on radiograph but 60% (12/20) had sonographic bridging callus (SBC) and when present all united (sensitivity 80%, specificity 100%, p = 0.002). At 12 weeks, bridging callus was present on both radiographs and ultrasound in all patients that united (n = 15, sensitivity 100%, specificity 100%, p < 0.001). No patient that developed a nonunion at six months post-injury had SBC at any time point. At six-weeks the absence of SBC had a positive predictive value for nonunion of 63% of patients (5/8) and by 12 weeks it was 100% (5/5). The SBC detection rated 'very strong' for intra- (kappa 0.92) and inter-observer agreement (kappa 0.84). The ICC of SBC at six-weeks with four blinded reviewers was 0.82 (95% confidence interval 0.68-0.91). CONCLUSIONS: This is the first study to establish time specific ultrasound fracture findings with a repeatable technique and assess the agreement between blinded reviewers.

What is the role of ultrasound in fracture management?: Diagnosis and therapeutic potential for fractures, delayed unions, and fracture-related infection.

OBJECTIVES: The aim of this study was to review the current evidence and future application for the role of diagnostic and therapeutic ultrasound in fracture management. METHODS: A review of relevant literature was undertaken, including articles indexed in PubMed with keywords "ultrasound" or "sonography" combined with "diagnosis", "fracture healing", "impaired fracture healing", "nonunion", "microbiology", and "fracture-related infection". RESULTS: The use of ultrasound in musculoskeletal medicine has expanded rapidly over the last two decades, but the diagnostic use in fracture management is not routinely practised. Early studies have shown the potential of ultrasound as a valid alternative to radiographs to diagnose common paediatric fractures, to detect occult injuries in adults, and for rapid detection of long bone fractures in the resuscitation setting. Ultrasound has also been shown to be advantageous in the early identification of impaired fracture healing; with the advent of 3D image processing, there is potential for wider adoption. Detection of implant-related infection can be improved by ultrasound mediated sonication of microbiology samples. The use of therapeutic ultrasound to promote union in the management of acute fractures is currently a controversial topic. However, there is strong in vitro evidence that ultrasound can stimulate a biological effect with potential clinical benefit in established nonunions, which supports the need for further investigation. CONCLUSION: Modern ultrasound image processing has the potential to replace traditional imaging modalities in several areas of trauma practice, particularly in the early prediction of impaired fracture healing. Further understanding of the therapeutic application of ultrasound is required to understand and identify the use in promoting fracture healing.Cite this article: J. A. Nicholson, S. T. J. Tsang, T. J. MacGillivray, F. Perks, A. H. R. W. Simpson. What is the role of ultrasound in fracture management? Diagnosis and therapeutic potential for fractures, delayed unions, and fracture-related infection. Bone Joint Res 2019;8:304-312. DOI: 10.1302/2046-3758.87.BJR-2018-0215.R2.

Routine fixation of displaced midshaft clavicle fractures is not cost-effective: a cost analysis from a randomized controlled trial.

AIMS: The primary aim of this study was to establish the cost-effectiveness of the early fixation of displaced midshaft clavicle fractures. PATIENTS AND METHODS: A cost analysis was conducted within a randomized controlled trial comparing conservative management (n = 92) versus early plate fixation (n = 86) of displaced midshaft clavicular fractures. The incremental cost-effectiveness ratio (ICER) was used to express the cost per quality-adjusted life-year (QALY). The Six-Dimension Short-Form Health Survey (SF-6D) score was used as the preference-based health index to calculate the cost per QALY at 12 months after the injury. RESULTS: The mean 12-month SF-6D was 0.9522 (95% confidence interval (CI) 0.9355 to 0.9689) following conservative management and 0.9607 (95% CI 0.9447 to 0.9767) following fixation, giving an advantage for fixation of 0.0085, which was not statistically significant (p = 0.46). The mean cost per patient was £1322.69 for conservative management and £5405.32 for early fixation. This gave an ICER of £480 309.41 per QALY. For a threshold of £20 000 per QALY, the benefit of fixation would need to be present for 24 years to be cost-effective compared with conservative treatment. Linear regression analysis identified nonunion as the only factor to adversely influence the SF-6D at 12 months (p < 0.001). CONCLUSION: Routine plate fixation of displaced midshaft clavicular fractures is not cost-effective. Nonunion following conservative management has an increased morbidity with comparable expense to early fixation. This may suggest that a targeted approach of fixation in patients who are at higher risk of nonunion would be more cost-effective than the routine fixation of all displaced fractures. Cite this article: Bone Joint J 2019;101-B:995-1001.

Cost-effectiveness and satisfaction following arthroscopic rotator cuff repair: does age matter?.

AIMS: The aim of this study was to investigate the influence of age on the cost-effectiveness of arthroscopic rotator cuff repair. PATIENTS AND METHODS: A total of 112 patients were prospectively monitored for two years after arthroscopic rotator cuff repair using the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH), the Oxford Shoulder Score (OSS), and the EuroQol five-dimension questionnaire (EQ-5D). Complications and use of healthcare resources were recorded. The incremental cost-effectiveness ratio (ICER) was used to express the cost per quality-adjusted life-year (QALY). Propensity score-matching was used to compare those aged below and above 65 years of age. Satisfaction was determined using the Net Promoter Score (NPS). Linear regression was used to identify variables that influenced the outcome at two years postoperatively. RESULTS: A total of 92 patients (82.1%) completed the follow-up. Their mean age was 59.5 years (sd 9.7, 41 to 78). There were significant improvements in the mean DASH (preoperative 47.6 vs one-year 15.3; p < 0.001) and OSS scores (26.5 vs 40.5; p < 0.001). Functional improvements were maintained with no significant change between one and two years postoperatively. The mean preoperative EQ-5D was 0.54 increasing to 0.81 at one year (p < 0.001) and maintained at 0.86, two years postoperatively. There was no significant difference between those aged below or above 65 years of age with regards to postoperative shoulder function or EQ-5D gains. Smoking was the only characteristic that significantly adversely influenced the EQ-5D at two years postoperatively (p = 0.005). A total of 87 were promoters and five were passive, giving a mean NPS of 95 (87/92). The total mean cost per patient was £3646.94 and the mean EQ-5D difference at one year was 0.2691, giving a mean ICER of £13 552.36/QALY. At two years, this decreased further to £5694.78/QALY. This was comparable for those aged below or above 65 years of age (£5209.91 vs £5525.67). Smokers had an ICER that was four times more expensive. CONCLUSION: Arthroscopic rotator cuff repair results in excellent patient satisfaction and cost-effectiveness, regardless of age. Cite this article: Bone Joint J 2019;101-B:860-866.

Differences in Fecal Gut Microbiota, Short-Chain Fatty Acids and Bile Acids Link Colorectal Cancer Risk to Dietary Changes Associated with Urbanization Among Zimbabweans.

The incidence of colorectal cancer (CRC) is gradually rising in sub-Saharan Africa. This may be due to dietary changes associated with urbanization, which may induce tumor-promoting gut microbiota composition and function. We compared fecal microbiota composition and activity in 10 rural and 10 urban Zimbabweans for evidence of a differential CRC risk. Dietary intake was assessed by a food frequency questionnaire. Fecal microbiota composition, metabolomic profile, functional microbial genes were analyzed, and bile acids and short chain fatty acids quantified. Animal protein intake was higher among urban volunteers, but carbohydrate and fiber intake were similar. Bacteria related to Blautia obeum, Streptococcus bovis, and Subdoligranulum variabile were higher in urban residents, whereas bacteria related to Oscillospira guillermondii and Sporobacter termitidis were higher in rural volunteers. Fecal levels of primary bile acids, cholic acid, and chenodeoxycholic acid (P < 0.05), and secondary bile acids, deoxycholic acid (P < 0.05) and ursodeoxycholic acid (P < 0.001) were higher in urban residents. Fecal levels of acetate and propionate, but not butyrate, were higher in urban residents. The gut microbiota composition and activity among rural and urban Zimbabweans retain significant homogeneity (possibly due to retention of dietary fiber), but urban residents have subtle changes, which may indicate a higher CRC risk.