Patient-centred measurement of recovery from day-case surgery using wrist worn accelerometers: a pilot and feasibility study.

This pilot and feasibility study evaluated wrist-worn accelerometers to measure recovery from day-case surgery in comparison with daily quality of recovery-15 scores. The protocol was designed with extensive patient and public involvement and engagement, and delivered by a research network of anaesthesia trainees. Forty-eight patients recruited through pre-operative assessment clinics wore wrist accelerometers for 7 days before (pre-operative) and immediately after elective surgery (early postoperative), and again at 3 months (late postoperative). Validated activity and quality of recovery questionnaires were administered. Raw accelerometry data were archived and analysed using open source software. The mean (SD) number of valid days of accelerometer wear per participant in the pre-operative, early and late postoperative periods were 5.4 (1.7), 6.6 (1.1) and 6.6 (1.0) days, respectively. On the day after surgery, Euclidian norm minus one (a summary measure of raw accelerations), step count, light physical activity and moderate/vigorous physical activity decreased to 57%, 47%, 59% and 35% of baseline values, respectively. Activity increased progressively on a daily basis but had not returned to baseline values by 7 days. Patient questionnaires suggested subjective recovery by postoperative day 3 to 4; however, accelerometry data showed that activity levels had not returned to baseline at this point. All activity measures had returned to baseline by 3 months. Wrist-worn accelerometery is acceptable to patients and feasible as a surrogate measure for monitoring postoperative recovery from day-case surgery. Our results suggest that patients may overestimate their rate of recovery from day-case surgery, which has important implications for future research.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Effect of the circumferential resection margin on survival following rectal cancer surgery.

BACKGROUND: The aim was to determine the effect of the circumferential resection margin (CRM) on overall survival following surgical excision of rectal cancer. METHODS: The effect of CRM on survival was examined by case mix-adjusted analysis of patients undergoing potentially curative excision of a rectal cancer between 1998 and 2002. RESULTS: Of 1896 patients, 1561 (82.3 per cent) had recorded data on the CRM. In 232 patients (14.9 per cent) tumour was found 1 mm or less from the CRM. In 370 patients (23.7 per cent) it was over 1 mm but no more than 5 mm from the CRM, and in 288 (18.4 per cent) it was over 5 mm but no more than 10 mm from the CRM. The remaining 671 patients (43.0 per cent) had a CRM exceeding 10 mm. Overall 5-year survival rates for these groups were 43.2, 51.7, 66.6 and 66.0 per cent respectively. Compared with patients with a CRM exceeding 10 mm, the adjusted risk of death was significantly increased for patients with a CRM of 1 mm or less (hazard ratio (HR) 1.61, P < 0.001) and those with a margin greater than 1 mm but no larger than 5 mm (HR 1.35, P = 0.005). There was no added risk for patients with tumour more than 5 mm but 10 mm or less from the CRM (HR 1.02, P = 0.873). The adverse effect of a CRM greater than 1 mm but no larger than 5 mm was found particularly in mid-rectal cancers. CONCLUSION: A predicted CRM of 5 mm or less on preoperative staging should be considered for neoadjuvant treatment.

Volume-outcome analysis of colorectal cancer-related outcomes.

BACKGROUND: Significant associations between caseload and surgical outcomes highlight the conflict between local cancer care and the need for centralization. This study examined the effect of hospital volume on short-term outcomes and survival, adjusting for the effect of surgeon caseload. METHODS: Between 1998 and 2002, 8219 patients with colorectal cancer were identified in a regional population-based audit. Outcomes were assessed using univariable and multivariable analysis to allow case mix adjustment. Surgeons were categorized as low (26 or fewer operations annually), medium (27-40) or high (more than 40) volume. Hospitals were categorized as low (86 or fewer), medium (87-109) or high (more than 109) volume. RESULTS: Some 7411 (90.2 per cent) of 8219 patients underwent surgery with an anastomotic leak rate of 2.9 per cent (162 of 5581), perioperative mortality rate of 8.0 per cent (591 of 7411) and 5-year survival rate of 46.8 per cent. Medium- and high-volume surgeons were associated with significantly better operative mortality (odds ratio (OR) 0.74, P = 0.010 and OR 0.66, P = 0.002 respectively) and survival (hazard ratio (HR) 0.88, P = 0.003 and HR 0.93, P = 0.090 respectively) than low-volume surgeons. Rectal cancer survival was significantly better in high-volume versus low-volume hospitals (HR 0.85, P = 0.036), with no difference between medium- and low-volume hospitals (HR 0.96, P = 0.505). CONCLUSION: This study has confirmed the relevance of minimum volume standards for individual surgeons. Organization of services in high-volume units may improve survival in patients with rectal cancer.

Thrombolysis or primary angioplasty? Reperfusion therapy for myocardial infarction in the UK.

Intravenous thrombolysis and percutaneous coronary intervention (PCI) are alternative treatment options for coronary reperfusion in acute myocardial infarction. Recent trials and meta-analyses have produced increasing evidence that primary coronary intervention produces better long-term outcomes for the treatment of acute myocardial infarction. Most of these studies, however, were performed in US or European healthcare systems and may not be directly transferable to an NHS setting. The widespread introduction of primary PCI would have major implications for the organisation of healthcare provision within the UK. An alternative to PCI that may produce similar outcomes at a reduced cost might be early (pre-hospital) administration of thrombolysis. In an era of unprecedented financial attention, the importance of interventions that are simultaneously beneficial to the patient and economical to the NHS has never been more important. The evidence base for primary PCI and its possible use in the NHS are discussed.

Involvement of surgical trainees in surgery for colorectal cancer and their effect on outcome.

OBJECTIVE: Surgical training in the UK is undergoing substantial changes. This study assessed: 1) the training opportunities available to trainees in operations for colorectal cancer, 2) the effect of colorectal specialization on training, and 3) the effect of consultant supervision on anastomotic complications, postoperative stay, operative mortality and 5-year survival. METHOD: Unadjusted and adjusted comparisons of outcomes were made for unsupervised trainees, supervised trainees and consultants as the primary surgeon in 7411 operated patients included in the Northern Region Colorectal Cancer Audit between 1998 and 2002. RESULTS: Surgery was performed in 656 (8.8%) patients by unsupervised trainees and in 1578 (21.3%) patients by supervised trainees. Unsupervised operations reduced from 182 (12.4%) in 1998 to 82 (6.1%) in 2002 (P < 0.001). Consultants with a colorectal specialist interest were more likely than nonspecialists to be present at surgical resections (OR 1.35, 1.12-1.63, P = 0.001) and to provide supervised training (OR 1.34, 1.17-1.53, P < 0.001). Patients operated on by unsupervised trainees were more often high-risk patients, however, consultant presence was not significantly associated with operative mortality (OR 0.83, 0.63-1.09, P = 0.186) or survival (HR 1.02, 0.92-1.13, P = 0.735) in risk-adjusted analysis. Supervised trainees had a case-mix similar to consultants, with shorter length of hospital stay (11.4 vs 12.4 days, P < 0.001), but similar mortality (OR 0.90, 0.71-1.16, 0.418) and survival (HR 0.96, 0.89-1.05, P = 0.378). CONCLUSION: One third of patients were operated on by trainees, who were more likely to perform supervised resections in colorectal teams. There was no difference in anastomotic leaks rates, operative mortality or survival between unsupervised trainees, supervised trainees and consultants when case-mix adjustment was applied. This study would suggest that there is considerable underused training capacity available.

Impact of surgeon volume and specialization on short-term outcomes in colorectal cancer surgery.

BACKGROUND: Several studies have shown a relationship between surgeon volume and outcomes in colorectal cancer surgery. The aim of this study was to determine the impact of surgeon volume and specialization on primary tumour resection rate, restoration of bowel continuity following rectal cancer resection, anastomotic leakage and perioperative mortality. METHODS: The Northern Region Colorectal Cancer Audit Group conducts a population-based audit of patients with colorectal cancer managed by surgeons. This study examined 8219 patients treated between 1998 and 2002. Outcomes were modelled using multivariate logistic regression analysis. RESULTS: Tumour resection was performed in 6949 (93.8 per cent) of 7411 patients. High-volume surgeons with an annual caseload of at least 18.5 (odds ratio (OR) 1.53 (95 per cent confidence interval (c.i.) 1.10 to 2.12); P = 0.012) and colorectal specialists (OR 1.42 (95 per cent c.i. 1.06 to 1.90); P = 0.018) were more likely to perform elective sphincter-saving rectal surgery. In elective surgery, the risk of perioperative death was lower for high-volume surgeons (OR 0.58 (95 per cent c.i. 0.44 to 0.76); P < 0.001), but this was not the case in emergency surgery. CONCLUSION: High-volume surgeons had lower perioperative mortality rates for elective surgery, and were more likely to use restorative rectal procedures.

Does cognitive function influence alaryngeal speech rehabilitation?

BACKGROUND: We sought to define the cognitive domains that influence valved speech rehabilitation. METHODS: Sixteen laryngectomees with primary tracheoesophageal punctures were randomly recruited from one head and neck unit. They were assessed by a consultant neuropsychologist and a speech therapist. Speech therapy time was determined from speech therapy notes. RESULTS: The Digit Symbol Substitution Test, assessing learning speed and processing speed, correlated significantly with speech therapy time in the first (p = .002) and third (p = .014) postoperative years, respectively. Categorical fluency assessment correlated positively with speech therapy time in the first year (p = .009). Learning speed (p = .007) and categorical fluency (p = .041) correlated positively with the fall in speech therapy input between the first and third year after laryngectomy. CONCLUSIONS: Learning speed, processing speed, and categorical fluency strongly influence alaryngeal speech rehabilitation. This study highlights the potential for pre-laryngectomy cognitive assessment to help plan alaryngeal speech rehabilitation. This has significant resource implications.

The cost-effectiveness of a new statin (rosuvastatin) in the UK NHS.

Statins are central to the government's National Service Framework (NSF) for coronary heart disease (CHD). NHS spending on statins is currently about pounds sterling 500 million per annum and rising at an annual rate of 30%. Although generally considered to be a cost-effective treatment for hyperlipidaemia and cardiovascular disease, given the high and rising expenditure on statins in the UK, there is a pressing need to ensure that the choice between available statins reflects cost-effectiveness considerations. A decision model was developed to establish the cost-effectiveness of treating new hypercholesterolaemic patients to UK and European target levels of blood total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C), using rosuvastatin, atorvastatin, simvastatin, pravastatin or fluvastatin. The model was used to estimate the proportion of patients reaching target and the associated costs over a one-year period from the perspective of the NHS. The effectiveness of the alternative statins were modelled using data from the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. Monte Carlo simulation was used to reflect uncertainty in the parameter estimates applied in the model. Rosuvastatin is demonstrated to dominate (i.e. lower costs and a higher number of patients treated to target) atorvastatin, simvastatin and pravastatin. Compared with fluvastatin, the incremental cost per additional patient to target (PTT) for rosuvastatin was pounds sterling 24 using LDL-C and pounds sterling 83 using TC. The probability that rosuvastatin is cost-effective exceeds 95%, provided the NHS is prepared to pay at least pounds sterling 35 per PTT to achieve target LDL-C cholesterol levels (pounds sterling 160 for TC). The analysis demonstrates rosuvastatin is more cost-effective than the other statins in achieving UK and European cholesterol targets.

Differentiated chondrocytes for cartilage tissue engineering.

Trauma to the articular cartilage surface of the joint represents a challenging clinical problem due to the very limited ability of this tissue to self-repair. Moreover, repair techniques such as microfracture, which introduce cells into the joint, have unpredictable clinical outcomes as they produce a fibrocartilage tissue that degenerates with time. Alternative treatments include tissue reconstruction with autograft and allograft tissue. However, these procedures are restricted by the availability of suitable donor tissue. These limitations have been the driving force behind the emerging field of articular cartilage tissue engineering. This paper will highlight and contrast the key challenges associated with the tissue engineering of this neo-tissue using differentiated adult cells. The various components of the tissue engineering process will be described including the choice of donor cell/tissue type and the selection of scaffolds that guide the formation of tissue. The ability of the tissue engineered implants to stimulate the repair of defects in vivo will also be discussed. Tissue engineering approaches may, in the future, provide an ideal alternative to the current surgical treatments for cartilage repair.

Scaffold-based three-dimensional human fibroblast culture provides a structural matrix that supports angiogenesis in infarcted heart tissue.

BACKGROUND: We have developed techniques to implant angiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulate revascularization of the damaged tissue. These experiments used a scaffold-based 3D human dermal fibroblast culture (3DFC) as an epicardial patch. The 3DFC contains viable cells that secrete angiogenic growth factors and has previously been shown to stimulate angiogenic activity. The hypothesis tested was that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarcted cardiac tissue. METHODS AND RESULTS: A coronary occlusion of a branch of the left anterior descending coronary artery was performed by thermal ligation in severe combined immunodeficient mice. 3DFCs with or without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardium at the site of tissue injury, and compared with animals that received infarct surgery but no implant. Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples were prepared for histology and cytochemistry. Fourteen and 30 days after surgery, the damaged myocardium receiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules, and capillaries) than nonviable and untreated control groups. CONCLUSIONS: In this animal model, viable 3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response in damaged tissue. Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged by infarction.

Insulin-like growth factor-I gene expression patterns during spontaneous repair of acute articular cartilage injury.

This study evaluated the constitutive insulin-like growth factor-I (IGF-I) gene expression pattern in spontaneously healing cartilage defects over the course of 16 weeks, and correlated the tissue morphology and matrix gene expression with IGF-I mRNA levels. Full-thickness 15 mm cartilage defects were debrided in the femoral trochlea of both femoropatellar joints of 8 horses and the healing defects examined 2, 4, 8, or 16 weeks after surgery. Samples were harvested for histologic assessment of tissue healing using H&E staining, toluidine blue histochemical reaction for proteoglycan deposition, and in situ hybridization and immunohistochemistry procedures to demonstrate collagen type II mRNA and protein expression. Total RNA was isolated for Northern analysis to measure cartilage matrix molecule expression, and for semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) to determine IGF-I gene expression patterns in healing cartilage defects. Full-thickness cartilage defects in horses were slow to heal compared to smaller lesions in similar locations in other animals. However, a progressive decline in tissue cellularity and vascularity, and increased tissue organization were observed on H&E stained specimens over the 16-week experiment. Evidence of early chondrogenic repair was detected through collagen type II in situ hybridization and immunohistochemistry. However, levels of collagen type II and aggrecan mRNA in lesions were not abundant on Northern analysis indicating incomplete chondrogenesis. IGF-I message expression followed a cyclic pattern with low levels at 2 weeks, followed by an increase at 4 and 8 weeks, and a subsequent decline at 16 weeks. There was no direct correlation between the stage of healing and cartilage matrix message expression, and the abundance of IGF-I mRNA in the healing lesions. In conclusion, this study demonstrated that the spontaneous healing of articular defects was accompanied by a temporal fluctuation in IGF-I gene expression which was discoordinate to the steady rise in expression of cartilage matrix molecules such as procollagen type II.

Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation.

Vascular endothelial cells (ECs) in vivo are subject to different flow conditions due to the variation in vessel geometry. The aim of this study is to elucidate the effects of different flow conditions on EC monolayer migration into a mechanically denuded zone and their underlying mechanisms. Both laminar and disturbed flows significantly enhanced EC migration. EC migration speed was the fastest under laminar flow, which preferentially promoted directional EC migration from the upstream side of the wounded monolayer. C3 exoenzyme (a Rho inhibitor) inhibited EC migration under static and flow conditions, and markedly reduced the effects of flow on EC migration. These results indicate that flow promotes EC migration through the Rho signaling pathway. Genistein (a tyrosine kinase inhibitor) selectively retarded EC migration under disturbed flow, suggesting that tyrosine phosphorylation may play a role in EC migration under disturbed flow. This study has demonstrated that different flow patterns differentially affect EC monolayer migration into the denuded zone involving multiple mechanisms.

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Formulation of PEG-based hydrogels affects tissue-engineered cartilage construct characteristics.

The limited supply of cartilage tissue with appropriate sizes and shapes needed for reconstruction and repair has stimulated research in the area of hydrogels as scaffolds for cartilage tissue engineering. In this study we demonstrate that poly(ethylene glycol) (PEG)-based semi-interpenetrating (sIPN) network hydrogels, made with a crosslinkable poly(ethylene glycol)-dimethacrylate (PEGDM) component and a non-crosslinkable interpenetration poly(ethylene oxide) (PEO) component, and seeded with chondrocytes support cartilage construct growth having nominal thicknesses of 6 mm and relatively uniform safranin-O stained matrix when cultured statically, unlike constructs grown with prefabricated macroporous scaffolds. Even though changing the molecular weight of the PEO from 100 to 20 kDa reduces the viscosity of the precursor polymer solution, we have demonstrated that it does not appear to affect the histological or biochemical characteristics of cartilaginous constructs. Extracellular matrix (ECM) accumulation and the spatial uniformity of the ECM deposited by the embedded chondrocytes decreased, and hydrogel compressive properties increased, as the ratio of the PEGDM:PEO in the hydrogel formulation increased (from 30:70 to 100:0 PEGDM:PEO). Total collagen and glycosaminoglycan contents per dry weight were highest using the 30:70 PEGDM:PEO formulation (24.4+/-3.5% and 7.1+/-0.9%, respectively). The highest equilibrium compressive modulus was obtained using the 100:0 PEGDM:PEO formulation (0.32+/-0.07 MPa), which is similar to the compressive modulus of native articular cartilage. These results suggest that the versatility of PEG-based sIPN hydrogels makes them an attractive scaffold for tissue engineering of cartilage.

Tissue engineering of vascular grafts.

The challenge of tissue engineering blood vessels with the mechanical properties of native vessels, and with the anti-thrombotic properties required is immense. Recent advances, however, indicate that the goal of providing a tissue-engineered vascular graft that will remain patent in vivo for substantial periods of time, is achievable. For instance, collagen gels have been used to fabricate a tissue in vitro that is representative of a native vessel: an acellular collagen tubular structure, when implanted as a vascular graft, was able to function, and to become populated with host cells. A completely cellular approach culturing cells into tissue sheets and wrapping these around a mandel was able to form a layered tubular structure with impressive strength. Culture of cells onto a biodegradable scaffold within a dynamic bioreactor, generated a tissue-engineered vascular graft with substantial stiffness and, when lined with endothelial cells, was able to remain patent for up to 4 weeks in vivo. In our experiments, use of a non-degradable polyurethane scaffold and culture with smooth muscle cells generated a construct with mechanical properties similar to native vessels. This composite tissue engineered vascular graft with an endothelial layer formed using fluid shear stress to align the endothelial cells, was able to remain patent with an neointima for up to 4 weeks. These results show that tissue engineering of vascular grafts has true potential for application in the clinical situation.

Separate lives, different interests: male and female reproduction in the Gambia.

We report the initial findings of a research programme on the fertility and reproductive health of both men and women in rural Gambia. The reproductive experiences of men and women in the population studied were very different. During the period 1993-97, the total fertility rates were 12.0 for men and 6.8 for women. For men fertility began later, reached higher levels and continued into older ages than for women. Through serial and polygynous marriages, men were able to extend their reproduction beyond what would be possible with one woman. Of the married men interviewed, 40% were married polygynously. Men's fertility preferences indicated that they recognized their reproductive potentials to be greater than those of their individual wives. On average, married men desired 15.2 children for themselves and 7.3 for each wife. In this polygynous population the means available for attaining reproductive goals were different for the two sexes, depending on the separate lives and different interests of men and women.

Mitogen-activated protein kinase signaling in bovine articular chondrocytes in response to fluid flow does not require calcium mobilization.

In the present study, the role of mitogen-activated protein kinases (MAPKs) in chondrocyte mechanotransduction was investigated. We hypothesized that MAPKs participate in fluid flow-induced chondrocyte mechanotransduction. To test our hypothesis, we studied cultured chondrocytes subjected to a well-defined mechanical stimulus generated with a laminar flow chamber. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) were activated 1.6-3-fold after 5-15 min of fluid flow exposure corresponding to a chamber wall shear stress of 1.6 Pa. Activation of ERK1/2 was observed in the presence of both 10% FBS and 0.1% BSA, suggesting that the flow effects do not require serum agonists. Treatment with thapsigargin or EGTA had no significant effect on the ERK1/2 activation response to flow, suggesting that Ca2+ mobilization is not required for this response. To assess downstream effects of the activated MAPKs on transcription, flow studies were performed using chondrocytes transfected with a chimeric luciferase construct containing 2.4 kb of the promoter region along with exon 1 of the human aggrecan gene. Two-hour exposure of transfected chondrocytes to fluid flow significantly decreased aggrecan promoter activity by 40%. This response was blocked by treatment of chondrocytes with the MEK-1 inhibitor PD98059. These findings demonstrate that, under the conditions of the present study, fluid flow-induced signals activate the MEK-1/ERK signaling pathway in articular chondrocytes, leading to down-regulation of expression of the aggrecan gene.