A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability.

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.

Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. METHODS: Quality-of-life (EuroQoL-5D-3L) and resource data were collected as part of the BLISTER trial: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis was performed using bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline- with prednisolone-initiated therapy [net cost £959, 95% confidence interval (CI) -£24 to £1941; net QALYs -0·024, 95% CI -0·088 to 0·041]. However, the findings varied by baseline blister severity. For patients with mild or moderate blistering (≤ 30 blisters) net costs and outcomes were similar. For patients with severe blistering (> 30 blisters) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0·090 QALYs, 95% CI -0·22 to 0·042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1·5% at a willingness to pay of £20 000 per QALY. CONCLUSIONS: Consistently with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering.

Evidence based treatment for unstable slipped upper femoral epiphysis: Systematic review and exploratory patient level analysis.

The management of slipped upper femoral epiphysis is controversial and evolving as insight into the condition develops. Loder introduced the concept of slip stability and demonstrated a strong association between poor outcome and instability. Almost half of patients with unstable slip developed femoral head osteonecrosis. This has been influential in surgeons' choice of treatments. Some surgeons have adopted a minimal intervention approach such as pinning in situ or gentle reduction and pinning whereas others advocated an urgent open reduction and stabilisation of slip using various surgical techniques. In this review we analysed the influence of various interventions, timing of surgery and severity of the slip on the outcome of unstable slip.

Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

Ciclosporin compared with prednisolone therapy for patients with pyoderma gangrenosum: cost-effectiveness analysis of the STOP GAP trial.

BACKGROUND: Pyoderma gangrenosum (PG) is a painful, ulcerating skin disease with poor evidence for management. Prednisolone and ciclosporin are the most commonly used treatments, although not previously compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of ciclosporin and prednisolone-initiated treatment for patients with PG. METHODS: Quality of life (QoL, EuroQoL five dimensions three level questionnaire, EQ-5D-3L) and resource data were collected as part of the STOP GAP trial: a multicentre, parallel-group, observer-blind RCT. Within-trial analysis used bivariate regression of costs and quality-adjusted life years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case analysis, when compared with prednisolone, ciclosporin was cost-effective due to a reduction in costs [net cost: -£1160; 95% confidence interval (CI) -2991 to 672] and improvement in QoL (net QALYs: 0·055; 95% CI 0·018-0·093). However, this finding appears driven by a minority of patients with large lesions (≥ 20 cm2 ) (net cost: -£5310; 95% CI -9729 to -891; net QALYs: 0·077; 95% CI 0·004-0·151). The incremental cost-effectiveness of ciclosporin for the majority of patients with smaller lesions was £23 374/QALY, although the estimate is imprecise: the probability of being cost-effective at a willingness-to-pay of £20 000/QALY was 43%. CONCLUSIONS: Consistent with the clinical findings of the STOP GAP trial, patients with small lesions should receive treatment guided by the side-effect profiles of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, ciclosporin-initiated treatment may be more cost-effective for patients with large lesions.

Antibiotic use in acute pancreatitis: An audit of current practice in a tertiary centre.

INTRODUCTION: Intravenous antibiotic prophylaxis is not recommended in acute pancreatitis. According to current international guidelines antibiotics together with further intervention should be considered in the setting of infected necrosis. Appropriate antibiotic therapy particularly avoiding over-prescription is important. This study examines antibiotic use in acute pancreatitis in a tertiary centre using the current IAP/APA guidelines for reference. METHODS: Data were collected on a consecutive series of patients admitted with acute pancreatitis over a 12 month period. Data were dichotomized by patients admitted directly to the centre and tertiary transfers. Information was collected on clinical course with specific reference to antibiotic use, episode severity, intervention and outcome. RESULTS: 111 consecutive episodes of acute pancreatitis constitute the reported population. 31 (28%) were tertiary transfers. Overall 65 (58.5%) patients received antibiotics. Significantly more tertiary transfer patients received antibiotics. Mean person-days of antibiotic use was 23.9 (sd 29.7) days in the overall study group but there was significantly more use in the tertiary transfer group as compared to patients having their index admission to the centre (40.9 sd 37.1 vs 10.2 sd 8.9; P < 0.005). Thirty four (44%) of patients with clinically mild acute pancreatitis received antibiotics. CONCLUSIONS: There is substantial use of antibiotics in acute pancreatitis, in particular in patients with severe disease. Over-use is seen in mild acute pancreatitis. Better consideration must be given to identification of prophylaxis or therapy as indication. In relation to repeated courses of antibiotics in severe disease there must be clear indications for use.

The SSTARS (STeroids and Stents Against Re-Stenosis) Trial: Different stent alloys and the use of peri-procedural oral corticosteroids to prevent in-segment restenosis after percutaneous coronary intervention.

BACKGROUND: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. METHODS: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. RESULTS: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. CONCLUSION: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349).

Colorectal cancer with synchronous hepatic metastases: Systematic review of reports comparing synchronous surgery with sequential bowel-first or liver-first approaches.

BACKGROUND: The management of colorectal cancer with synchronous liver-limited metastases currently lacks randomised trial evidence to inform case selection for any of the bowel-first, liver-first or synchronous surgery routes. We examine the literature to report outcome data from reports utilising all three approaches. METHODS: A systematic review was conducted using OvidSP (including Embase, EBM Reviews and MEDLINE databases) to find articles reporting discrete peri-operative and long-term outcomes for patients undergoing sequential bowel-first, liver-first surgery or synchronous liver and bowel surgery. RESULTS: Of 223 unique citations, 3 cohort studies were identified comprising a pooled population of 1203 patients who completed treatment protocols between 1982 and 2011. Patients were allocated to bowel-first surgery (748 patients, 62.2%), liver-first surgery (75, 6.2%) or synchronous liver/bowel surgery (380, 31.6%). Minor complications were similar between procedures. Major complications were consistent with a pooled fixed estimate of 9.1% (95%CI: 7.6%-10.8%, I(2) = 48%). Post-operative death was rare and consistent with a pooled fixed effect estimate of 3.1% (95%CI: 2.2%-4.3%, I(2) = 0%). Median follow-up ranged from 25.1 to 40.0 months, with a pooled underlying 5-year survival fixed effect estimate of 44% (I(2) = 39%). CONCLUSION: This review assesses outcomes of patients with colorectal cancer with synchronous liver metastases managed by either synchronous, sequential liver-first or bowel-first surgery. Overall treatment-related mortality is low and survival is similar among the three groups. These findings provide support for the continued use of all three pathways until better evidence to guide selection of an individual treatment option is available.

Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy.

Understanding the signaling differences that distinguish human HER2-amplified (HER2-positive (HER2+)) breast cancers from other breast cancer subtypes may help to identify protein drug targets for the specific treatment of HER2+ breast cancers. We performed two kinome-wide small interfering RNA (siRNA) screens on five HER2+ breast cancer cell lines, seven breast cancer cell lines in which HER2 was not amplified and two normal breast cell lines. To pinpoint the main kinases driving HER2 signaling, we performed a comprehensive siRNA screen that identified loss of the HER2/HER3 heterodimer as having the most prominent inhibitory effect on the growth of HER2+ breast cancer cells. In a second siRNA screen focused on identifying genes that could sensitize HER2+ cells to trastuzumab treatment, we found that loss of signaling members downstream of phosphatidylinositol 3 kinase (PI3K) potentiated the growth inhibitory effects of trastuzumab. Loss of HER2 and HER3, as well as proteins involved in mitogenic and environmental stress pathways inhibited the proliferation of HER2+ cells only in the absence of trastuzumab, suggesting that these pathways are inhibited by trastuzumab treatment. Loss of essential G2/M cell cycle mediators or proteins involved in vesicle organization exerted inhibitory effects on HER2+ cell growth that were unaffected by trastuzumab. Furthermore, the use of a sensitization index (SI) identified targeting the PI3K pathway to sensitize to trastuzumab treatment. Antagonism using the SI identified MYO3A, MYO3B and MPZL1 as antagonizers to trastuzumab treatment among HER2+ cell lines. Our results suggest that the dimerization partners of HER2 are important for determining the activation of downstream proliferation pathways. Understanding the complex layers of signaling triggered downstream of HER2 homodimers and heterodimers will facilitate the selection of better targets for combination therapies intended to treat HER2+ breast cancers.

A prospective trial of temporary sacral nerve stimulation for constipation associated with neurological disease.

AIM: This study assessed the effectiveness of temporary sacral nerve stimulation (SNS) in patients with constipation associated with neurological disease using an off-on-off design, and evaluated the long-term response in patients undergoing permanent SNS. METHOD: Patients with chronic constipation associated with neurological disease receiving specialist clinic care at the University Hospital North Durham over a 2-year period were recruited to a trial of SNS. Recordings of bowel function were made for 6 weeks (baseline) and a temporary electrode was then inserted and recordings were made for the next 3 weeks (stimulation). The electrodes were then removed and assessment was continued for a further 3 weeks (posttreatment). Patient-completed questionnaires were used to determine the severity of constipation (Global Assessment of Symptoms, Constipation, GA Constipation), symptoms (Patient Assessment of Constipation Symptoms score, PAC-SYM) and quality-of-life (Patient Assessment of Constipation-Quality Of Life score, PAC-QOL; European Quality of Life-Five-Domain score; European Quality of Life-Visual Analogue Score). Information was obtained on bowel function and medication. Physiological data were also available for transit and laser Doppler flow cytometry to measure mucosal blood flow. RESULTS: Twenty-two patients were recruited, of whom 18 completed the trial. GA Constipation reduced significantly during temporary SNS: -1.09 (95% CI -1.59 to -0.59; P = 0.0003). PAC-SYM and PAC-QOL scores showed similar improvements. There was also a significant fall in the time spent in the toilet (P = 0.04) and a decrease in laxative use (P = 0.03). Twelve (67%) patients responded to temporary SNS and received a permanent implant with long-term success in 50%. CONCLUSION: Sacral nerve stimulation can be effective in treating some patients with refractory severe neuroconstipation. A response to temporary SNS may predict long-term benefit in only half the patients undergoing permanent SNS.

A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement.

Intravenous tranexamic acid (TXA) has been shown to be effective in reducing blood loss and the need for transfusion after joint replacement. Recently, there has been interest in applying it topically before the closure of surgical wounds. This has the advantages of ease of application, maximum concentration at the site of bleeding, minimising its systemic absorption and, consequently, concerns about possible side-effects. We conducted a systematic review and meta-analysis which included 14 randomised controlled trials (11 in knee replacement, two in hip replacement and one in both) which investigated the effect of topical TXA on blood loss and rates of transfusion. Topical TXA significantly reduced the rate of blood transfusion (total knee replacement: risk ratio (RR) 4.51; 95% confidence interval (CI): 3.02 to 6.72; p < 0.001 (nine trials, I(2) = 0%); total hip replacement: RR 2.56; 95% CI: 1.32 to 4.97, p = 0.004 (one trial)). The rate of thromboembolic events with topical TXA were similar to those found with a placebo. Indirect comparison of placebo-controlled trials of topical and intravenous TXA indicates that topical administration is superior to the intravenous route. In conclusion, topical TXA is an effective and safe method of reducing the need for blood transfusion after total knee and hip replacement. Further research is required to find its optimum dose for topical use.

Cardiopulmonary exercise testing for preoperative risk assessment before pancreaticoduodenectomy for cancer.

OBJECTIVE: Pancreaticoduodenectomy is the standard of care for tumors confined to the head of pancreas and can be undertaken with low operative mortality. The procedure has a high morbidity, particularly in older patient populations with preexisting comorbidities. This study evaluated the role of cardiopulmonary exercise testing to predict postoperative morbidity and outcome in high-risk patients undergoing pancreaticoduodenectomy. METHODS: In a prospective cohort of consecutive patients undergoing pancreaticoduodenectomy, those aged over 65 years (or younger with comorbidity) were categorized as high risk and underwent preoperative assessment by cardiopulmonary exercise testing (CPET) according to a predefined protocol. Data were collected on functional status, postoperative complications, and survival. RESULTS: A total of 143 patients underwent preoperative assessment, 50 of whom were deemed to be at low risk for surgery per study protocol. Of 93 high-risk patients, 64 proceeded to surgery after preoperative CPET. Neither anaerobic threshold (AT) nor maximal oxygen consumption ([Formula: see text] O 2 MAX) predicted patient mortality or morbidity. However, ventilatory equivalent of carbon dioxide ([Formula: see text] E/[Formula: see text] CO 2) at AT was a predictive marker of postoperative mortality, with an area under the curve (AUC) of 0.84 (95 % confidence interval [CI] 0.63-1.00, p = 0.020); a threshold of 41 was 75 % sensitive and 95 % specific (positive predictive value 50 %, negative predictive value 98 %). Above this threshold, raised [Formula: see text] E/[Formula: see text] CO 2 predicted poor long-term survival (hazard ratio 2.05, 95 % CI 1.09-3.86, p = 0.026). CONCLUSIONS: CPET is a useful adjunctive test for predicting postoperative outcome in patients being assessed for pancreaticoduodenectomy. Raised CPET-derived [Formula: see text] E/[Formula: see text] CO 2 predicts early postoperative death and poor long-term survival.

PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling.

It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells.

Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify the molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells, in which a selected gene was stably knocked down were injected into the tail veins of mice, and the formation of tumors in the lungs was monitored. One of the several genes found to be important for tumor growth in the lungs was NIMA-related kinases 2 (Nek2), a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad. In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 has a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

Topical treatments for chronic plaque psoriasis of the scalp: a systematic review.

BACKGROUND: Chronic plaque psoriasis is the most common type of psoriasis and is characterized by redness, thickness and scaling. First-line management is with topical treatments. OBJECTIVES: Our objective was to establish the effectiveness, tolerability and safety of topical treatments for people with chronic plaque psoriasis of the scalp, assessing placebo-controlled trials of all treatments and head-to-head trials that assessed vitamin D analogues. METHODS: As part of a Cochrane review of topical treatments for psoriasis, we systematically searched electronic databases for randomized controlled trials. The review included 26 randomized controlled trials of treatments for psoriasis of the scalp with 8020 participants. Trials used several measures to assess changes in psoriasis severity: these were combined using the standardized mean difference metric and interpreted by reporting as a six-point global improvement score. RESULTS: On effectiveness grounds, very potent or potent steroid treatments should be preferred to vitamin D3 analogue with approximately an average 10% additional improvement on a six-point scale. Vitamin D3 analogue combined with potent steroid appears slightly more effective than potent steroid monotherapy (3% additional improvement on a six-point scale). Rates of withdrawal from treatment and adverse events in trials were generally low and similar to those for placebo. There remains uncertainty about the atrophic potential of corticosteroid treatments for scalp psoriasis. CONCLUSIONS: Corticosteroids are more effective than vitamin D analogues and similarly tolerated. However, further research is needed to inform long-term maintenance treatment and provide appropriate safety data.

Cardiopulmonary exercise testing for preoperative risk assessment before hepatic resection.

BACKGROUND: Contemporary liver surgery practice must accurately assess operative risk in increasingly elderly populations with greater co-morbidity. This study evaluated preoperative cardiopulmonary exercise testing (CPET) in high-risk patients undergoing hepatic resection. METHODS: In a prospective cohort referred for liver resection, patients aged over 65 years (or younger with co-morbidity) were evaluated by preoperative CPET. Data were collected prospectively on functional status, postoperative complications and survival. RESULTS: Two hundred and four patients were assessed for hepatic resection, of whom 108 had preoperative CPET. An anaerobic threshold (AT) of 9·9 ml O(2) per kg per min predicted in-hospital death and subsequent survival. Below this value, AT was 100 per cent sensitive and 76 per cent specific for in-hospital mortality, with a positive predictive value (PPV) of 19 per cent and a negative predictive value (NPV) of 100 per cent: no deaths occurred above the threshold. Age and respiratory efficiency in the elimination of carbon dioxide (VE/VCO(2)) at AT were statistically significant predictors of postoperative complications. Receiver operating characteristic (ROC) curve analysis showed that a threshold of 34·5 for VE/VCO(2) at AT provided a specificity of 84 per cent and a sensitivity of 47 per cent, with a PPV of 76 (95 per cent confidence interval (c.i.) 58 to 88) per cent and a NPV of 60 (48 to 72) per cent for postoperative complications. Long-term survival of those with an AT of less than 9·9 ml O(2) per kg per min was significantly worse than that of patients with a higher AT (hazard ratio for mortality 1·81, 95 per cent c.i. 1·04 to 3·17; P = 0·036). CONCLUSION: CPET provides a useful prognostic adjunct in the preoperative assessment of patients undergoing hepatic resection.

Tranexamic acid in total knee replacement: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of randomised controlled trials evaluating the effect of tranexamic acid (TXA) upon blood loss and transfusion in primary total knee replacement. The review used the generic evaluation tool designed by the Cochrane Bone, Joint and Muscle Trauma Group. A total of 19 trials were eligible: 18 used intravenous administration, one also evaluated oral dosing and one trial evaluated topical use. TXA led to a significant reduction in the proportion of patients requiring blood transfusion (risk ratio (RR) 2.56, 95% confidence interval (CI) 2.1 to 3.1, p < 0.001; heterogeneity I(2) = 75%; 14 trials, 824 patients). Using TXA also reduced total blood loss by a mean of 591 ml (95% CI 536 to 647, p < 0.001; I(2) = 78%; nine trials, 763 patients). The clinical interpretation of these findings is limited by substantial heterogeneity. However, subgroup analysis of high-dose (> 4 g) TXA showed a plausible consistent reduction in blood transfusion requirements (RR 5.33; 95% CI 2.44 to 11.65, p < 0.001; I(2) = 0%), a finding that should be confirmed by a further well-designed trial. The current evidence from trials does not support an increased risk of deep-vein thrombosis (13 trials, 801 patients) or pulmonary embolism (18 trials, 971 patients) due to TXA administration.

Incentivizing preventive services in primary care: perspectives on Local Enhanced Services.

BACKGROUND: General practitioners in the UK play a key role in prevention but provision of preventive services is variable. The 2004 General Medical Services contract allows Primary Care Trusts (PCTs) to address health needs through providing locally agreed payments for Local Enhanced Services (LESs). This study identifies how this contractual flexibility is used for preventive services and explores its perceived effectiveness. METHODS: Semi-structured interviews were carried out (2008-09) in 10 purposively selected case study sites in England. Details of LESs for these sites were collected (2009) through Freedom of Information requests or local contacts. A national on-line survey of PCTs (2009) provided a national context for case study findings. RESULTS: LESs were considered to be effective in incentivizing preventive activity. However, specifications and performance management were often weak, awareness of how to optimize incentives was low and, as optional services, LESs were perceived to be at risk in a financial downturn. CONCLUSIONS: Using LESs for preventive services highlights gaps in 'core' primary care responsibilities and in the national pay-for-performance framework. Current incentive arrangements are complex, could increase inequalities and provide only a partial, short-term solution to developing a proactive approach to prevention in primary care.