A medium-chain fatty acid analogue prevents hepatosteatosis and decreases inflammatory lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis.

BACKGROUND: Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis. METHODS: Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro. RESULTS: In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both ß- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake. CONCLUSIONS: SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both ß- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.

PR1P, a VEGF-stabilizing peptide, reduces injury and inflammation in acute lung injury and ulcerative colitis animal models.

Acute Respiratory Distress Syndrome (ARDS) and Ulcerative Colitis (UC) are each characterized by tissue damage and uncontrolled inflammation. Neutrophils and other inflammatory cells play a primary role in disease progression by acutely responding to direct and indirect insults to tissue injury and by promoting inflammation through secretion of inflammatory cytokines and proteases. Vascular Endothelial Growth Factor (VEGF) is a ubiquitous signaling molecule that plays a key role in maintaining and promoting cell and tissue health, and is dysregulated in both ARDS and UC. Recent evidence suggests a role for VEGF in mediating inflammation, however, the molecular mechanism by which this occurs is not well understood. We recently showed that PR1P, a 12-amino acid peptide that binds to and upregulates VEGF, stabilizes VEGF from degradation by inflammatory proteases such as elastase and plasmin thereby limiting the production of VEGF degradation products (fragmented VEGF (fVEGF)). Here we show that fVEGF is a neutrophil chemoattractant in vitro and that PR1P can be used to reduce neutrophil migration in vitro by preventing the production of fVEGF during VEGF proteolysis. In addition, inhaled PR1P reduced neutrophil migration into airways following injury in three separate murine acute lung injury models including from lipopolysaccharide (LPS), bleomycin and acid. Reduced presence of neutrophils in the airways was associated with decreased pro-inflammatory cytokines (including TNF-α, IL-1ß, IL-6) and Myeloperoxidase (MPO) in broncho-alveolar lavage fluid (BALF). Finally, PR1P prevented weight loss and tissue injury and reduced plasma levels of key inflammatory cytokines IL-1ß and IL-6 in a rat TNBS-induced colitis model. Taken together, our data demonstrate that VEGF and fVEGF may each play separate and pivotal roles in mediating inflammation in ARDS and UC, and that PR1P, by preventing proteolytic degradation of VEGF and the production of fVEGF may represent a novel therapeutic approach to preserve VEGF signaling and inhibit inflammation in acute and chronic inflammatory diseases.

Incidence and development of cholestasis in surgical neonates receiving an intravenous mixed-oil lipid emulsion.

BACKGROUND: Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. METHODS: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). RESULTS: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. CONCLUSION: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

Effects of systemic anticoagulation in a murine model of compensatory lung growth.

BACKGROUND: Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). METHODS: Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. RESULTS: UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. CONCLUSIONS: UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. IMPACT: Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.

Structurally-engineered fatty acid 1024 (SEFA-1024) improves diet-induced obesity, insulin resistance, and fatty liver disease.

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

Racial and Socioeconomic Disparities in Necrotizing Soft-Tissue Infection.

Necrotizing soft-tissue infection (NSTI) is a medical emergency. We investigated the impact of racial, socioeconomic disparities, and comorbidities on mortality, complications, length of stay, and charges in patients with NSTI.Data were acquired from the National Inpatient Sample from Q4 2015 to 2017. ICD-10, Clinical Modification codes were utilized to identify relevant cases. Logistic regression was used to assess socioeconomic, racial, and health risk factors for adverse outcomes in NSTI patients.Of 16,071,053 cases identified during the study period, 15,078 (0.094%) NSTI cases were recognized. Black patients had increased odds of amputation (OR 1.40 95% CI 1.24-1.58, p < 0.001), prolonged hospital stay (OR 1.40 95% CI 1.24-1.58, p < 0.001), excessive charges (OR 1.22 95% CI 1.03-1.43, p = 0.019), and adverse discharge disposition (OR 1.32 95% CI 1.19-1.46, p < 0.001) compared to white patients. Hispanic patients had increased odds of mortality (OR 1.30 95% CI 1.05-1.60, p = 0.014) and amputation (OR 1.21 95% CI 1.04-1.42, p = 0.016) compared to white patients. Medicare patients had increased odds of mortality (OR 1.35 95% CI 1.09-1.67, p = 0.006), Medicaid patients had increased odd of amputation (OR 1.33 95% CI 1.17-1.51, p < 0.001) and prolonged LOS (OR 1.33 95% CI 1.17-1.51, p < 0.001). Patients in the lower income quartiles had decreased odds of amputation compared to the highest income quartile, including the 26th to 50th income quartile (OR 0.84 95% CI 0.73-0.98, p = 0.022) and 51st to 75th income quartile (OR 0.84 95% CI 0.73-0.98, p = 0.022).Racial and socioeconomic disparities exist for patients being treated for NSTIs.

Deficiency in pigment epithelium-derived factor accelerates pulmonary growth and development in a compensatory lung growth model.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.

Investigation of the mechanisms of VEGF-mediated compensatory lung growth: the role of the VEGF heparin-binding domain.

Morbidity and mortality for neonates with congenital diaphragmatic hernia-associated pulmonary hypoplasia remains high. These patients may be deficient in vascular endothelial growth factor (VEGF). Our lab previously established that exogenous VEGF164 accelerates compensatory lung growth (CLG) after left pneumonectomy in a murine model. We aimed to further investigate VEGF-mediated CLG by examining the role of the heparin-binding domain (HBD). Eight-week-old, male, C57BL/6J mice underwent left pneumonectomy, followed by post-operative and daily intraperitoneal injections of equimolar VEGF164 or VEGF120, which lacks the HBD. Isovolumetric saline was used as a control. VEGF164 significantly increased lung volume, total lung capacity, and alveolarization, while VEGF120 did not. Treadmill exercise tolerance testing (TETT) demonstrated improved functional outcomes post-pneumonectomy with VEGF164 treatment. In lung protein analysis, VEGF treatment modulated downstream angiogenic signaling. Activation of epithelial growth factor receptor and pulmonary cell proliferation was also upregulated. Human microvascular lung endothelial cells (HMVEC-L) treated with VEGF demonstrated decreased potency of VEGFR2 activation with VEGF121 treatment compared to VEGF165 treatment. Taken together, these data indicate that the VEGF HBD contributes to angiogenic and proliferative signaling, is required for accelerated compensatory lung growth, and improves functional outcomes in a murine CLG model.

Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.

PR1P Stabilizes VEGF and Upregulates Its Signaling to Reduce Elastase-induced Murine Emphysema.

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.

Laparoscopic Transabdominal Colopexy for Prolapse of a Newborn End Colostomy: A Novel Technique.

Background: Prolapse can occur in up to 20% of newborn end colostomies and may be associated with significant morbidities that require operative intervention. Prolapse repair is traditionally performed through an open parastomal or laparotomy incision. We report on 2 cases that utilized a novel laparoscopic transabdominal colopexy technique, which offered a minimally invasive solution uniquely suited to neonates and infants while obviating the morbidity of open reoperative surgery. Materials and Methods: Retrospective review of 2 patients at a single center undergoing a laparoscopic transabdominal colopexy for end colostomy prolapse. The primary outcome measure was prolapse recurrence. Secondary outcomes included intraoperative or immediate postoperative complications. Results: Both patients who underwent the laparoscopic transabdominal colopexy procedure had prolapsed end colostomies. There were no intraoperative or immediate postoperative complications. Both patients had no additional episodes of recurrence during the follow-up period. One patient has since had their colostomy reversed without complications. Conclusion: We present our initial results in the utilization of a novel technique for repair of a newborn end colostomy prolapse-laparoscopic transabdominal colopexy. Our technique thus far has demonstrated success in preventing recurrent prolapse through a minimally invasive technique with no significant morbidity.

Is there a role for rehabilitation streaming following total knee arthroplasty? Preliminary insights from a randomized controlled trial.

OBJECTIVE: To determine whether total knee arthroplasty recipients demonstrating comparatively poor mobility at entry to rehabilitation and who received supervised therapy, had better rehabilitation outcomes than those who received less supervision. DESIGN: Retrospective analysis of randomized trial data. PATIENTS: Total knee arthroplasty participants randomized to supervised (n = 159) or home-based therapy (n = 74). METHODS: Participants were dichotomized based on mean target 6-min walk test (6MWT) pre-therapy (second post-surgical week). Absolute and change in 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscales amongst low performers in the supervised (n = 89) and unsupervised (n = 36) groups were compared, as were high performers in the supervised (n = 70) and unsupervised (n = 38) groups. RESULTS: Low performers in the unsupervised compared with the supervised group demonstrated significantly poorer 6MWT scores (absolute δ = 8.5%, p = 0.003; change δ = 8.1%, p = 0.007) when therapy ceased (10 weeks post-surgery). No differences in 6MWT were observed between the high performing subgroups or in the recovery of WOMAC subscales between any subgroups. CONCLUSION: Individuals manifesting comparatively poor mobility at the commencement of physiotherapy may recover their mobility, but not perceived function, more quickly if streamed to supervised therapy.

One-to-one therapy is not superior to group or home-based therapy after total knee arthroplasty: a randomized, superiority trial.

BACKGROUND: The aim of this study was to determine whether center-based, one-to-one physical therapy provides superior outcomes compared with group-based therapy or a simple monitored home-based program in terms of functional and physical recovery and health-related quality of life after total knee arthroplasty. METHODS: Patients awaiting primary total knee arthroplasty at two Sydney metropolitan hospitals were enrolled into this prospective, randomized, superiority trial preoperatively. At two weeks postoperatively, participants were randomly allocated to one of three six-week treatment programs (twelve one-to-one therapy sessions, twelve group-based therapy sessions, or a monitored home program) with use of a computer-generated sequence. Self-reported outcomes (Oxford Knee Score, Western Ontario and McMaster Universities Osteoarthritis Index pain and function subscales, and Medical Outcomes Study 12-Item Short-Form Survey) and performance-based functional outcomes were measured over twelve months postoperatively by a blinded assessor. The primary outcome was knee pain and function measured with use of the Oxford Knee Score at ten weeks postoperatively. Intention-to-treat analysis was conducted. RESULTS: Two hundred and forty-nine patients (eighty-five who had one-to-one therapy, eighty-four who had group-based therapy, and eighty who were in the monitored home program) were randomized and 233 were available for their one-year follow-up assessment. Participants who received one-to-one therapy did not have a superior Oxford Knee Score at week ten compared with those who received the alternative interventions; the median score was 32 points for the one-to-one therapy group, 36 points for the group-based therapy group, and 34 points for the monitored home program group (p = 0.20). Furthermore, one-to-one therapy was not superior compared with group-based therapy or monitored home program in improving any of the secondary outcomes across the first postoperative year. No adverse events were associated with any of the treatment arms. CONCLUSIONS: One-to-one therapy does not provide superior self-reported or performance-based outcomes compared with group-based therapy or a monitored home program, in the short term and the long term after total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic level I. See Instructions for Authors for a complete description of levels of evidence.

The six-minute walk test is an excellent predictor of functional ambulation after total knee arthroplasty.

BACKGROUND: The Six-minute walk (6 MW) and Timed-Up-and-Go (TUG) are short walk tests commonly used to evaluate functional recovery after total knee arthroplasty (TKA). However, little is known about walking capacity of TKA recipients over extended periods typical of everyday living and whether these short walk tests actually predict longer, more functional distances. Further, short walk tests only correlate moderately with patient-reported outcomes. The overarching aims of this study were to compare the performance of TKA recipients in an extended walk test to healthy age-matched controls and to determine the utility of this extended walk test as a research tool to evaluate longer term functional mobility in TKA recipients. METHODS: The mobility of 32 TKA recipients one year post-surgery and 43 healthy age-matched controls were assessed using the TUG, 6 MW and 30-minute walk (30 MW) tests. The latter test was repeated one week later. Self-reported function was measured using the WOMAC Index and a physical activity questionnaire. RESULTS: 30 MW distance was significantly shorter amongst TKA recipients (mean 2108 m [95% CI 1837 to 2381 m]; Controls 3086 m [2981 to 3191 m], P < 0.001). Test-retest repeatability was high (ICC = 0.97, TKA; 0.96, Controls). Amongst TKA recipients, the 30 MW distance correlated strongly with the shorter tests (6 MW, r = 0.97, P < 0.001; TUG, r = -0.82, P < 0.001). Multiple regression modeling found 6 MW distance to be the only significant predictor (P < 0.001) of 30 MW distance, explaining 96% of the variability. The TUG test models were moderate predictors of WOMAC function (55%) and physical activity (36%) and were stronger predictors than 6 MW and 30 MW tests. CONCLUSIONS: Though TKA recipients are able to walk for 30 minutes one year post-surgery, their performance falls significantly short of age-matched norms. The 30 MW test is strongly predicted by 6 MW test performance, thus providing strong construct validity for the use of the 6 MW test in the TKA population. Neither a short nor long walk test is a strong predictor of patient-reported function after TKA.

Tourniquet application only during cement fixation in total knee arthroplasty: a double-blind, randomized controlled trial.

BACKGROUND: The functional benefits of tourniquet application for short periods compared with standard duration applications during total knee arthroplasty surgery have not been well explored. We aimed to compare functional outcomes between tourniquet application of short duration (during cement fixation only) and tourniquet application of longer duration (from skin incision to just after cement fixation). METHODS: We planned to randomize 230 patients to short and long duration groups. The primary outcome was Oxford Knee Score at 10 weeks post-surgery. In-hospital blood transfusion rate was also a primary safety measure. Serial measures of knee function were taken together with knee range, quadriceps lag and timed stair tests. RESULTS: The trial was discontinued after randomization of 65 patients. Interim analysis indicated a higher risk of transfusion (odds ratio 7.38, P= 0.015) in the short duration group. No significant difference was observed in Oxford Knee Score at 10 weeks. There were no between-group differences in rate of recovery up to 52 weeks for any outcome. CONCLUSIONS: Restricting tourniquet application to the period of cementing is associated with a significantly higher risk of transfusion. This approach is impractical if it is not offset by gains in functional recovery.

Heart rate response and factors affecting exercise performance during home- or class-based rehabilitation for knee replacement recipients: lessons for clinical practice.

OBJECTIVES: Patients undergoing total knee replacement (TKR) are typically de-conditioned and manifest medical co-morbidities associated with a lack of fitness. Consequently, an argument exists for rehabilitation programmes to target cardiovascular fitness. Doubt exists, however, as to the capacity of TKR recipients to exercise intensely and effectively. This preliminary study aimed to: (1) determine whether patients participating in a home- or class-based exercise programme can exercise in their heart rate (HR) training zone, and (2) identify confounding factors influencing performance. METHODS: A mixed method study nested within a randomized trial was undertaken. Forty-two people (mean age 70 years; 23 women) randomized to commence a 6-week group-based (GRP) or monitored home-based programme (MHP) 2 weeks post surgery participated. Assessments were undertaken weeks 5 (GRP and MHP) and 8 (GRP only) post surgery. HR and participant perceived exertion (PE, 0-10 point scale) captured exercise intensity. Qualitative description using triangulation of informant sources identified factors influencing exercise performance. RESULTS: For both programmes, attainment of training HR was almost universal (93% or more), average time spent above the training HR exceeded 30 minutes, and PE indicated moderate exertion (5/10). Individual inconsistency in time spent above the training HR was evident between testing weeks in GRP participants. Therapist skill and focus, and patient co-morbidity, knee pain and stiffness and willingness were confounders of performance. CONCLUSION: TKR recipients participating in exercise programmes can exercise moderately hard indicating a potential for rehabilitation to improve cardiovascular fitness. Whether individual fitness actually improves likely depends in part on therapist recognition of key modifiable factors. It is recommended that therapists use these observations to inform practice so patients extract the most benefit from their rehabilitation.

Is discharge knee range of motion a useful and relevant clinical indicator after total knee replacement? Part 1.

OBJECTIVES: Knee range of motion (ROM) at the point of discharge from acute care is used as a clinical indicator to benchmark performance between hospital services after total knee replacement (TKR). The utility of the current benchmark, including whether discharge ROM varies between hospitals, is unknown. This study aimed to determine whether the benchmark [≥80 degrees flexion and ≤5 degrees fixed flexion (extension)] is realistic and whether the service provider is a predictor of knee ROM. METHODS: A prospective, observational cohort study was conducted involving 176 TKR patients from four hospitals. Knee ROM was photographically assessed preoperatively and at discharge. 'Hospital', typical patient demographic data and preoperative ROM were identified a priori as potential predictors of knee ROM. RESULTS: Overall, 2% [95% CI (confidence interval) 1-6] of patients attained the ROM benchmark. Individual hospital attainment of the benchmark ranged 0-7% with a significant difference (P = 0.047) evident between the best performer and the remaining hospitals. The overall rates of attainment of the individual flexion (25%, 95% CI 19-32) and extension (15%, 95% CI 10-21) components were similarly low, although the scatter between hospitals was large [flexion (2-47%); extension (8-44%)]. Preoperative flexion and hospital were significant (P = 0.002) predictors of discharge flexion, explaining 21% of the variance. Similarly, hospital and preoperative extension together with gender were significant (P < 0.001) predictors of discharge extension, explaining 26% of the variance. CONCLUSIONS: A small minority of patients attained the knee ROM benchmark, indicating the existing standard is unrealistic. Nevertheless, that 'hospital' is an important predictor confirms the potential of ROM for benchmarking purposes. Differences in physiotherapy practices may contribute to inter-hospital variation in discharge knee ROM together with other undefined factors. The causal relationships explaining the variation and the relationship between discharge ROM and longer-term outcome are avenues for future exploration which will help define the clinical relevance of the indicator.

Is discharge knee range of motion a useful and relevant clinical indicator after total knee replacement? Part 2.

OBJECTIVE: Knee range of motion (ROM) at discharge from acute care is used as a clinical indicator following total knee replacement (TKR) surgery. This study aimed to assess the clinical relevance of this indicator by determining whether discharge knee ROM predicts longer-term knee ROM and patient-reported knee pain and function. METHODS: A total of 176 TKR recipients were prospectively followed after discharge from acute care. Outcomes assessed included knee ROM and Oxford knee score post rehabilitation and 1 year post surgery. Discharge ROM and other patient factors were identified a priori as potential predictors in multiple linear regression modelling. RESULTS: A total of 133 (76%) and 141 (80%) patients were available for follow-up post rehabilitation [mean postoperative week 8.1 (SD 2.7)] and at 1 year [mean postoperative month 12.1 (SD 1.4)], respectively. Greater discharge knee flexion was a significant (P < 0.001) predictor of greater post-rehabilitation flexion but not 1-year knee flexion (P < 0.083). Better discharge knee extension was a significant predictor of better post-rehabilitation (P = 0.001) and 1-year knee extension (P = 0.013). Preoperative Oxford score and post-rehabilitation knee flexion independently predicted post-rehabilitation Oxford score, and gender predicted 1-year Oxford score. Discharge ROM did not significantly predict Oxford score in either model. CONCLUSION: The finding that early knee range predicts longer-term range provides clinical evidence favouring the relevance of discharge knee ROM as a clinical indicator. Although longer-term patient-reported knee pain and function were not directly associated with discharge knee ROM, they were associated with ROM when measured concurrently in the sub-acute phase. No causal effect has been demonstrated, but the findings suggest it may be important for physiotherapists to maximize range in the early and sub-acute periods.

Improvements in knee range and symptomatic and functional behavior after knee arthroplasty based on preoperative restriction in range.

Recovery of knee range and Oxford Knee Score post knee arthroplasty based on preoperative knee range is described. A total of 191 patients recruited across 5 hospitals were assessed preoperatively, at 8 weeks postoperatively and 1 year. Preoperative knee range was categorized into "low" (≤ 109), "moderate" (> 109 to ≤ 120), and "high" (> 120°) flexion and "normal" (± -5) and "restricted" (> +5°) terminal extension. Recovery was analyzed using MIXED modeling procedures. The low-flexion group gained flexion across time. The moderate-flexion and high-flexion groups lost flexion initially then recovered, but 1-year flexion remained lower than preoperative values. The restricted terminal extension group gained extension across time. The normal terminal extension group lost extension initially then recovered to preoperative values at 1 year. Recovery in Oxford score was independent of preoperative knee range limitation. Improvement in knee range postoperatively, but not self-reported behavior, is highly dependent on the initial restriction in range.

Validity and reliability of using photography for measuring knee range of motion: a methodological study.

BACKGROUND: The clinimetric properties of knee goniometry are essential to appreciate in light of its extensive use in the orthopaedic and rehabilitative communities. Intra-observer reliability is thought to be satisfactory, but the validity and inter-rater reliability of knee goniometry often demonstrate unacceptable levels of variation. This study tests the validity and reliability of measuring knee range of motion using goniometry and photographic records. DESIGN: Methodology study assessing the validity and reliability of one method ('Marker Method') which uses a skin marker over the greater trochanter and another method ('Line of Femur Method') which requires estimation of the line of femur. SETTING: Radiology and orthopaedic departments of two teaching hospitals. PARTICIPANTS: 31 volunteers (13 arthritic and 18 healthy subjects). Knee range of motion was measured radiographically and photographically using a goniometer. Three assessors were assessed for reliability and validity. MAIN OUTCOMES: Agreement between methods and within raters was assessed using concordance correlation coefficient (CCCs). Agreement between raters was assessed using intra-class correlation coefficients (ICCs). 95% limits of agreement for the mean difference for all paired comparisons were computed. RESULTS: Validity (referenced to radiographs): Each method for all 3 raters yielded very high CCCs for flexion (0.975 to 0.988), and moderate to substantial CCCs for extension angles (0.478 to 0.678). The mean differences and 95% limits of agreement were narrower for flexion than they were for extension. Intra-rater reliability: For flexion and extension, very high CCCs were attained for all 3 raters for both methods with slightly greater CCCs seen for flexion (CCCs varied from 0.981 to 0.998). Inter-rater reliability: For both methods, very high ICCs (min to max: 0.891 to 0.995) were obtained for flexion and extension. Slightly higher coefficients were obtained for flexion compared to extension, and with the Marker compared to the Line of Femur Method. For intra- and inter-rater reliability, the mean differences (within 2 degrees) and 95% limits of agreement (within 5 degrees) were generally clinically acceptable for both methods. CONCLUSION: Photography potentially offers a superior method of measurement over standard goniometry as visualising the centre of the knee is simplified in a two-dimensional plane and the permanent record provides greater assessor transparency as well as opportunity to confer. The Marker and Line of Femur Methods have moderate to substantial validity, but the inter- and intra-rater repeatability for trained observers are excellent with both methods yielding small mean differences with narrow limits of agreement. The Line of Femur Method offers the added advantage that it does not rely on inter-clinician consistency in identifying the greater trochanter.