Context-Specific Function of the Engineered Peptide Domain of PHP.B.

One approach to improve the utility of adeno-associated virus (AAV)-based gene therapy is to engineer the AAV capsid to (i) overcome poor transport through tissue barriers and (ii) redirect the broadly tropic AAV to disease-relevant cell types. Peptide- or protein-domain insertions into AAV surface loops can achieve both engineering goals by introducing a new interaction surface on the AAV capsid. However, we understand little about the impact of insertions on capsid structure and the extent to which engineered inserts depend on a specific capsid context to function. Here, we examine insert-capsid interactions for the engineered variant AAV9-PHP.B. The 7-amino-acid peptide insert in AAV9-PHP.B facilitates transport across the murine blood-brain barrier via binding to the receptor Ly6a. When transferred to AAV1, the engineered peptide does not bind Ly6a. Comparative structural analysis of AAV1-PHP.B and AAV9-PHP.B revealed that the inserted 7-amino-acid loop is highly flexible and has remarkably little impact on the surrounding capsid conformation. Our work demonstrates that Ly6a binding requires interactions with both the PHP.B peptide and specific residues from the AAV9 HVR VIII region. An AAV1-based vector that incorporates a larger region of AAV9-PHP.B-including the 7-amino-acid loop and adjacent HVR VIII amino acids-can bind to Ly6a and localize to brain tissue. However, unlike AAV9-PHP.B, this AAV1-based vector does not penetrate the blood-brain barrier. Here we discuss the implications for AAV capsid engineering and the transfer of engineered activities between serotypes. IMPORTANCE Targeting AAV vectors to specific cellular receptors is a promising strategy for enhancing expression in target cells or tissues while reducing off-target transgene expression. The AAV9-PHP.B/Ly6a interaction provides a model system with a robust biological readout that can be interrogated to better understand the biology of AAV vectors' interactions with target receptors. In this work, we analyzed the sequence and structural features required to successfully transfer the Ly6a receptor-binding epitope from AAV9-PHP.B to another capsid of clinical interest, AAV1. We found that AAV1- and AAV9-based vectors targeted to the same receptor exhibited different brain-transduction profiles. Our work suggests that, in addition to attachment-receptor binding, the capsid context in which this binding occurs is important for a vector's performance.

The use of 3.15% chlorhexidine gluconate/70% alcohol hub disinfection to prevent central line-associated bloodstream infections in dialysis patients.

PURPOSE: Preventing CLABSI events in the dialysis inpatient population represents significant challenges. Bacteremia associated with lines or grafts are common health-associated infections that lead to adverse patient outcomes. Dialysis patients represent a much higher infection risk due to health frequency needs, more frequent hospitalizations, multiple comorbidity issues, fistula functionality, and multiple attempts for line access leading to additional complications, costs, morbidity, and mortality. METHODS: An observational study was conducted including central line device days, CLABSI events, and possible confounding variables in admitted dialysis patients. All CLABSI data were identified according to the Centers for Disease Control and Prevention's National Healthcare Safety Network's definitions for CLABSIs. The intervention involved the removal of 70% alcohol swabs and alcohol hub disinfecting caps, then replacing with swabs containing 3.15% chlorhexidine gluconate/70% alcohol for central line hub disinfection and vascular graft access skin disinfection. RESULTS: The 5-year preintervention period (2008-2012) involved 7568 central line days, 11 CLABSI events, and a 1.45 per 1000 device day rate. The 6-month trial period involved 1559 central line days and no CLABSI events. The 5-year postimplementation period (2013-2017) involved 9787 central line days, 5 CLABSI events, and a 0.51 per 1000 device day rate. The postimplementation period represented a statistically significant (P value=0.0493) reduction with 65% fewer CLABSI events compared with the preimplementation period. LIMITATIONS: A limitation was variations in scrub time and dry time during central venous catheter hub access. While we were comparing 2 products, behavioral practices using these 2 products were possible influencers and represent a possible confounding variable. CONCLUSIONS: This study found that using alcohol with chlorhexidine gluconate prior to accessing central line hubs and vascular grafts allows for reduction in CLABSI events and sustains statistically significant lower CLABSI rates in the inpatient dialysis population. HIGHLIGHTS Using alcohol with chlorhexidine gluconate (CHG) before accessing central line hubs helps reduce central line-associated bloodstream infection (CLABSI) events Using alcohol with CHG before accessing vascular grafts helps reduce CLABSI events A statistically significant reduction (65%) in CLABSI events occurred after use. Statistically significant lower CLABSI rates are sustainable with use of alcohol with CHG.

The percentage of high-grade prostatic adenocarcinoma in prostate biopsies significantly improves on Grade Groups in the prediction of prostate cancer death.

AIMS: It has been recommended that the percentage of high-grade (HG) Gleason patterns 4 and 5 should be quantified in prostate cancer. However, this has not been assessed in a cohort using prostate cancer death as an outcome, and there is debate as to whether the biopsy with the 'worst' percentage of HG disease or an 'overall' percentage of HG disease should be reported. Such data may assist in active surveillance decisions. METHODS AND RESULTS: Men with clinically localised prostate cancer diagnosed by needle biopsy from 1990 to 2003 were included. The endpoint was prostate cancer death. Clinical variables included Gleason score (GS), prostate-specific antigen level, age, clinical stage, and disease extent. Deaths were divided into those from prostate cancer and those from other causes, according to World Health Organization criteria. Nine hundred and eighty-eight biopsy cases were centrally reviewed according to criteria agreed at the Chicago International Society of Urological Pathology conference in 2014. Cores were given individual GSs and Grade Groups (GGs), and a percentage of each grade was given for each core. Both the worst percentage of HG disease seen in a biopsy series and overall percentage of HG disease were calculated. The overall percentage of HG disease was highly significant, with a hazard ratio of 4.45 for the interquartile range (95% confidence interval 3.30-6.01, P < 2.2 × 10-16 ), and was similar to the percentage of HG disease seen in the worst core. In multivariate analysis, both were highly significant. GG2 cases with ≤5% Gleason pattern 4 showed similar survival to GG1 cases. CONCLUSIONS: These data validate the use of percentage of HG disease to predict prostate cancer death. As both worst and overall percentage of HG disease are powerful predictors of outcome, either could be chosen to provide prognostic information.

How Well Do Inexpensive, Portable Pulse Oximeter Values Agree with Arterial Oxygenation Saturation in Acutely Ill Patients?

The purpose of this study was to examine the level of agreement between a portable SpO2 device and the clinical gold standard SaO2 in intermediate care patients.

Evidence for differences in patterns of temporal trends in meta-analyses of diagnostic accuracy studies in the Cochrane Database of Systematic Reviews.

OBJECTIVES: Temporal trends in comparative meta-analyses of interventions are well-recognised in the medical literature. For studies of diagnostic test accuracy (DTA), evidence of temporal trends is growing and the importance of assessing and reporting them has been highlighted in recent guidelines on post-market surveillance in several jurisdictions. In this study we evaluate the prevalence and patterns of time trends using a larger and more up-to-date set of DTA systematic reviews than has previously been examined, from the Cochrane Database of Systematic Reviews. STUDY DESIGN AND SETTING: Cumulative meta-analysis was conducted on bivariate random effects meta-analysis estimates of sensitivity and specificity, after ranking studies by publication date. Trends for all studies were assessed graphically using plots of summary estimates by study rank, and using ROC plots of sensitivity vs. specificity. Linear trends were also described using weighted linear regression with autocorrelated errors of summary estimates against study rank. Various patterns of non-linear trends were characterised descriptively. RESULTS: The analysis included 46 reviews (92 meta-analyses) conducted between 2017 and 2022. The total number of studies within all reviews was 1,486, with a median [IQR] 7,134 [2,782, 16,406] participants per review. Reviews had a median [IQR] time span of 19 [15,25] publication years. Time trends in at least one DTA measure were observed in 40 (87%) reviews, and statistically significant linear trends in 32 (71%) reviews. Non-linear time trends were observed in 16 (35%) reviews. There was no evidence for a trend in either DTA measure in 27 (59%) reviews. CONCLUSION: The study contributes evidence on the variety in patterns of linear and non-linear temporal DTA trends which has not previously been described. We recommended researchers check statistical assumptions of trend analysis methods, for example using graphical methods. Further research into potential reasons for time trends could contribute to the robustness of future meta-analyses.

Recommendations for Method Development and Validation of qPCR and dPCR Assays in Support of Cell and Gene Therapy Drug Development.

The emerging use of qPCR and dPCR in regulated bioanalysis and absence of regulatory guidance on assay validations for these platforms has resulted in discussions on lack of harmonization on assay design and appropriate acceptance criteria for these assays. Both qPCR and dPCR are extensively used to answer bioanalytical questions for novel modalities such as cell and gene therapies. Following cross-industry conversations on the lack of information and guidelines for these assays, an American Association of Pharmaceutical Scientists working group was formed to address these gaps by bringing together 37 industry experts from 24 organizations to discuss best practices to gain a better understanding in the industry and facilitate filings to health authorities. Herein, this team provides considerations on assay design, development, and validation testing for PCR assays that are used in cell and gene therapies including (1) biodistribution; (2) transgene expression; (3) viral shedding; (4) and persistence or cellular kinetics of cell therapies.

Characterization of expression and prognostic implications of transforming growth factor beta, programmed death-ligand 1, and T regulatory cells in canine histiocytic sarcoma.

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm in dogs. Expression and prognostic significance of transforming growth factor beta (TGF-ß), programmed death-ligand 1 (PD-L1), and T regulatory cells (Tregs) in HS is unknown. The goal of this study was to investigate the expression and prognostic significance of TGF-ß, PD-L1, and FoxP3/CD25 in canine HS utilizing RNA in situ hybridization (RNAscope®). After validation was performed, RNAscope® on formalin-fixed paraffin-embedded (FFPE) patient HS tissue samples was performed for all targets and expression quantified with HALO® software image analysis. Cox proportional hazard model was conducted to investigate the association between survival time and each variable. Additionally, for categorical data, the Kaplan-Meier product-limit method was used to generate survival curves. TGF-ß and PD-L1 mRNA expression was confirmed in the DH82 cell line by reverse transcription polymerase chain reaction (RT-PCR) and CD25 + FoxP3 + cells were detected by flow cytometry in peripheral blood. Once the RNAscope® method was validated, TGF-ß H-score and dots/cell and FoxP3 dots/cell were assessed in HS samples and found to be significantly correlated with survival. Moderate positive correlations were found between FoxP3 and PD-L1 H-score, percent staining area, and dots/cell, and FoxP3 and TGF-ß dots/cell. In summary, RNAscope® is a valid technique to detect TGF-ß and PD-L1 expression and identify Tregs in canine HS FFPE tissues. Furthermore, canine HS expresses TGF-ß and PD-L1. Increased TGF-ß and FoxP3 correlated with worse prognosis. Prospective studies are warranted to further investigate TGF-ß, PD-L1, and Tregs effect on prognosis.

Characterization of expression and prognostic implications of GD2 and GD3 synthase in canine histiocytic sarcoma.

GD2 and GD3 are disialoganglioside oncofetal antigens important in oncogenesis. GD2 synthase (GD2S) and GD3 synthase (GD3S) are needed for GD2 and GD3 production. The objectives of this study are to validate the use of RNA in situ hybridization (RNAscope®) in the detection of GD2S and GD3S in canine histiocytic sarcoma (HS) in vitro and optimize this technique in canine formalin-fixed paraffin-embedded (FFPE) tissues. A secondary objective is to evaluate the prognostic significance of GD2S and GD3S on survival. Quantitative RT-PCR compared GD2S and GD3S mRNA expression between three HS cell lines followed by RNAscope® in fixed cell pellets from the DH82 cell line and FFPE tissues. Variables prognostic for survival were determined with Cox proportional hazard model. RNAscope® was validated for detection of GD2S and GD3S and optimized in FFPE tissues. GD2S and GD3S mRNA expression was variable between cell lines. GD2S and GD3S mRNA expression was detected and measured in all tumor tissues; there was no association with prognosis. GD2S and GD3S are expressed in canine HS and successfully detected using the high throughput technique of RNAscope® in FFPE samples. This study provides the foundation for future prospective research of GD2S and GD3S utilizing RNAscope®.

Costs of Joint Replacement in Osteoarthritis: A Study Using the National Joint Registry and Clinical Practice Research Datalink Data Sets.

OBJECTIVE: To estimate the costs of primary hip and knee replacement in individuals with osteoarthritis up to 2 years postsurgery, compare costs before and after the surgery, and identify predictors of hospital costs. METHODS: Patients age ≥18 years with primary planned hip or knee replacements and osteoarthritis in England between 2008 and 2016 were identified from the National Joint Registry and linked with Hospital Episode Statistics data containing inpatient episodes. Primary care data linked with hospital outpatient records were also used to identify patients age ≥18 years with primary hip or knee replacements between 2008 and 2016. All health care resource use was valued using 2016/2017 costs, and nonparametric censoring methods were used to estimate total 1-year and 2-year costs. RESULTS: We identified 854,866 individuals undergoing hip or knee replacement. The mean censor-adjusted 1-year hospitalization costs for hip and knee replacement were £7,827 (95% confidence interval [95% CI] 7,813, 7,842) and £7,805 (95% CI 7,790, 7,818), respectively. Complications and revisions were associated with up to a 3-fold increase in 1-year hospitalization costs. The censor-adjusted 2-year costs were £9,258 (95% CI 9,233, 9,280) and £9,452 (95% CI 9,430, 9,475) for hip and knee replacement, respectively. Adding primary and outpatient care, the mean total hip and knee replacement 2-year costs were £11,987 and £12,578, respectively. CONCLUSION: There are significant costs following joint replacement. Revisions and complications accounted for considerable costs and there is a significant incentive to identify best approaches to reduce these.

Cost-effectiveness of bilateral vs. single internal thoracic artery grafts at 10 years.

AIMS: Using bilateral internal thoracic arteries (BITAs) for coronary artery bypass grafting (CABG) has been suggested to improve survival compared to CABG using single internal thoracic arteries (SITAs) for patients with advanced coronary artery disease. We used data from the Arterial Revascularization Trial (ART) to assess long-term cost-effectiveness of BITA grafting compared to SITA grafting from an English health system perspective. METHODS AND RESULTS: Resource use, healthcare costs, and quality-adjusted life years (QALYs) were assessed across 10 years of follow-up from an intention-to-treat perspective. Missing data were addressed using multiple imputation. Incremental cost-effectiveness ratios were calculated with uncertainty characterized using non-parametric bootstrapping. Results were extrapolated beyond 10 years using Gompertz functions for survival and linear models for total cost and utility. Total mean costs at 10 years of follow-up were £17 594 in the BITA arm and £16 462 in the SITA arm [mean difference £1133 95% confidence interval (CI) £239 to £2026, P = 0.015]. Total mean QALYs at 10 years were 6.54 in the BITA arm and 6.57 in the SITA arm (adjusted mean difference -0.01 95% CI -0.2 to 0.1, P = 0.883). At 10 years, BITA grafting had a 33% probability of being cost-effective compared to SITA, assuming a cost-effectiveness threshold of £20 000. Lifetime extrapolation increased the probability of BITA being cost-effective to 51%. CONCLUSIONS: BITA grafting has significantly higher costs but similar quality-adjusted survival at 10 years compared to SITA grafting. Extrapolation suggests this could change over lifetime.

Enhanced recovery following hip and knee arthroplasty: a systematic review of cost-effectiveness evidence.

OBJECTIVES: To assess cost-effectiveness of enhanced recovery pathways following total hip and knee arthroplasties. Secondary objectives were to report on quality of studies and identify research gaps for future work. DESIGN: Systematic review of cost-utility analyses. DATA SOURCES: Ovid MEDLINE, Embase, the National Health Service Economic Evaluations Database and EconLit, January 2000 to August 2019. ELIGIBILITY CRITERIA: English-language peer-reviewed cost-utility analyses of enhanced recovery pathways, or components of one, compared with usual care, in patients having total hip or knee arthroplasties for osteoarthritis. DATA EXTRACTION AND SYNTHESIS: Data extracted by three reviewers with disagreements resolved by a fourth. Study quality assessed using the Consensus on Health Economic Criteria list, the International Society for Pharmacoeconomics and Outcomes Research and Assessment of the Validation Status of Health-Economic decision models tools; for trial-based studies the Cochrane Collaboration's tool to assess risk of bias. No quantitative synthesis was undertaken. RESULTS: We identified 17 studies: five trial-based and 12 model-based studies. Two analyses evaluated entire enhanced recovery pathways and reported them to be cost-effective compared with usual care. Ten pathway components were more effective and cost-saving compared with usual care, three were cost-effective, and two were not cost-effective. We had concerns around risk of bias for all included studies, particularly regarding the short time horizon of the trials and lack of reporting of model validation. CONCLUSIONS: Consistent results supported enhanced recovery pathways as a whole, prophylactic systemic antibiotics, antibiotic-impregnated cement and conventional ventilation for infection prevention. No other interventions were subject of more than one study. We found ample scope for future cost-effectiveness studies, particularly analyses of entire recovery pathways and comparison of incremental changes within pathways. A key limitation is that standard practices have changed over the period covered by the included studies. PROSPERO REGISTRATION NUMBER: CRD42017059473.

Five-year costs from a randomised comparison of bilateral and single internal thoracic artery grafts.

BACKGROUND: The use of bilateral internal thoracic arteries (BITA) for coronary artery bypass grafting (CABG) may improve survival compared with CABG using single internal thoracic arteries (SITA). We assessed the long-term costs of BITA compared with SITA. METHODS: Between June 2004 and December 2007, 3102 patients from 28 hospitals in seven countries were randomised to CABG surgery using BITA (n=1548) or SITA (n=1554). Detailed resource use data were collected from the initial hospital episode and annually up to 5 years. The associated costs of this resource use were assessed from a UK perspective with 5 year totals calculated for each trial arm and pre-selected patient subgroups. RESULTS: Total costs increased by approximately £1000 annually in each arm, with no significant annual difference between trial arms. Cumulative costs per patient at 5-year follow-up remained significantly higher in the BITA group (£18 629) compared with the SITA group (£17 480; mean cost difference £1149, 95% CI £330 to £1968, p=0.006) due to the higher costs of the initial procedure. There were no significant differences between the trial arms in the cost associated with healthcare contacts, medication use or serious adverse events. CONCLUSIONS: Higher index costs for BITA were still present at 5-year follow-up mainly driven by the higher initial cost with no subsequent difference emerging between 1 year and 5 years of follow-up. The overall cost-effectiveness of the two procedures, to be assessed at the primary endpoint of the 10-year follow-up, will depend on composite differences in costs and quality-adjusted survival. TRIAL REGISTRATION NUMBER: ISRCTN46552265.

Assessment on patient outcomes of primary hip replacement: an interrupted time series analysis from 'The National Joint Registry of England and Wales'.

OBJECTIVES: Effects of the UK Department of Health's national Enhanced Recovery After Surgery (ERAS) Programme on outcomes after primary hip replacement. DESIGN: Natural experimental study using interrupted time series to assess the changes in trends before, during and after ERAS implementation (April 2009 to March 2011). SETTING: Surgeries in the UK National Joint Registry were linked with Hospital Episode Statistics containing inpatient episodes from National Health Service trusts in England and patient reported outcome measures. PARTICIPANTS: Patients aged ≥18 years from 2008 to 2016. MAIN OUTCOME MEASURES: Regression coefficients of monthly means of length of hospital stay, bed day cost, change in Oxford Hip Scores (OHS) 6 months post-surgery, complications 6 months post-surgery and revision rates 5 years post-surgery. RESULTS: 438 921 primary hip replacements were identified. Hospital stays shortened from 5.6 days in April 2008 to 3.6 in December 2016. There were also improvements in bed day costs (£7573 in April 2008 to £5239 in December 2016), positive change in self-reported OHS from baseline to 6 months post-surgery (17.7 points in April 2008 to 22.9 points in December 2016), complication rates (4.1% in April 2008 to 1.7% March 2016) and 5 year revision rates (5.9 per 1000 implant-years (95% CI 4.8 to 7.2) in April 2008 to 2.9 (95% CI 2.2 to 3.9) in December 2011). The positive trends in all outcomes started before ERAS was implemented and continued during and after the programme. CONCLUSIONS: Patient outcomes after hip replacement have improved over the last decade. A national ERAS programme maintained this improvement but did not alter the existing rate of change.

Condom use among high-risk adolescents: anticipation of partner disapproval and less pleasure associated with not using condoms.

OBJECTIVE: We determined the association of demographic, psychosocial, and contextual factors with condom use among a large community sample of at-risk adolescents recruited from four locations in the U.S. METHODS: We enrolled 1,410 adolescents/young adults between the ages of 15 and 21 with a history of unprotected sex in the past 90 days at four study sites. Subjects completed an audio-assisted, computerized assessment that gathered information about sexual behavior and its contexts, substance use, and relevant risk and protective attitudes. RESULTS: Nearly two-thirds of adolescents did not use condoms at the time of last intercourse and adolescents reported a mean of 15.5 (median = 5) unprotected intercourse occasions in the past 90 days. Controlling for relevant demographic variables, not using condoms was associated with the perception that condoms reduce sexual pleasure, the perception that partners will not approve of condom use, and less discussion with partners about condoms. CONCLUSIONS: Even across racial/ethnic groups, gender, and geographic locations, several important correlates of adolescents' sexual risk reduction were identified. Many adolescents may feel that condoms reduce their sexual pleasure and fear partner reactions if they initiate condom use. These attitudes may be malleable through clinical and community-based interventions.

Cost-effectiveness of enhanced recovery in hip and knee replacement: a systematic review protocol.

INTRODUCTION: Hip and knee replacement represents a significant burden to the UK healthcare system. 'Enhanced recovery' pathways have been introduced in the National Health Service (NHS) for patients undergoing hip and knee replacement, with the aim of improving outcomes and timely recovery after surgery. To support policymaking, there is a need to evaluate the cost-effectiveness of enhanced recovery pathways across jurisdictions. Our aim is to systematically summarise the published cost-effectiveness evidence on enhanced recovery in hip and knee replacement, both as a whole and for each of the various components of enhanced recovery pathways. METHODS AND ANALYSIS: A systematic review will be conducted using MEDLINE, EMBASE, Econlit and the National Health Service Economic Evaluations Database. Separate search strategies were developed for each database including terms relating to hip and knee replacement/arthroplasty, economic evaluations, decision modelling and quality of life measures.We will extract peer-reviewed studies published between 2000 and 2017 reporting economic evaluations of preoperative, perioperative or postoperative enhanced recovery interventions within hip or knee replacement. Economic evaluations alongside cohort studies or based on decision models will be included. Only studies with patients undergoing elective replacement surgery of the hip or knee will be included. Data will be extracted using a predefined pro forma following best practice guidelines for economic evaluation, decision modelling and model validation.Our primary outcome will be the cost-effectiveness of enhanced recovery (entire pathway and individual components) in terms of incremental cost per quality-adjusted life year. A narrative synthesis of all studies will be presented, focussing on cost-effectiveness results, study design, quality and validation status. ETHICS AND DISSEMINATION: This systematic review is exempted from ethics approval because the work is carried out on published documents. The results of the review will be disseminated in a peer-reviewed academic journal and at conferences. PROSPERO REGISTRATION NUMBER: CRD42017059473.

Cost-effectiveness of the faecal immunochemical test at a range of positivity thresholds compared with the guaiac faecal occult blood test in the NHS Bowel Cancer Screening Programme in England.

OBJECTIVES: Through the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP), men and women in England aged between 60 and 74 years are invited for colorectal cancer (CRC) screening every 2 years using the guaiac faecal occult blood test (gFOBT). The aim of this analysis was to estimate the cost-utility of the faecal immunochemical test for haemoglobin (FIT) compared with gFOBT for a cohort beginning screening aged 60 years at a range of FIT positivity thresholds. DESIGN: We constructed a cohort-based Markov state transition model of CRC disease progression and screening. Screening uptake, detection, adverse event, mortality and cost data were taken from BCSP data and national sources, including a recent large pilot study of FIT screening in the BCSP. RESULTS: Our results suggest that FIT is cost-effective compared with gFOBT at all thresholds, resulting in cost savings and quality-adjusted life years (QALYs) gained over a lifetime time horizon. FIT was cost-saving (p<0.001) and resulted in QALY gains of 0.014 (95% CI 0.012 to 0.017) at the base case threshold of 180 µg Hb/g faeces. Greater health gains and cost savings were achieved as the FIT threshold was decreased due to savings in cancer management costs. However, at lower thresholds, FIT was also associated with more colonoscopies (increasing from 32 additional colonoscopies per 1000 people invited for screening for FIT 180 µg Hb/g faeces to 421 additional colonoscopies per 1000 people invited for screening for FIT 20 µg Hb/g faeces over a 40-year time horizon). Parameter uncertainty had limited impact on the conclusions. CONCLUSIONS: This is the first published economic analysis of FIT screening in England using data directly comparing FIT with gFOBT in the NHS BSCP. These results for a cohort starting screening aged 60 years suggest that FIT is highly cost-effective at all thresholds considered. Further modelling is needed to estimate economic outcomes for screening across all age cohorts simultaneously.

One-year costs of bilateral or single internal mammary grafts in the Arterial Revascularisation Trial.

OBJECTIVE: Coronary artery bypass grafting (CABG) using bilateral internal mammary arteries (BIMA) may improve survival over CABG using single internal mammary arteries (SIMA), but may be surgically more complex (and therefore costly) and associated with impaired sternal wound healing. We report, for the first time, a detailed comparison of healthcare resource use and costs over 12 months, as part of the Arterial Revascularisation (ART) Trial. METHODS: 3102 patients in 28 hospitals in seven countries were randomised to CABG surgery using BIMA (n=1548) or SIMA (n=1554). Detailed resource use data were collected covering surgery, the initial hospital episode, and for 12 months post randomisation. Using UK unit costs, total costs were calculated and compared between trial arms and for subgroups. RESULTS: Patients randomised to BIMA spent 20 min longer in theatre (95% CI 15 to 25, p<0.001) and also required more treatment for sternal wound problems. Mean (SD) total costs per patient at 12 months were £13 839 (£10 534) for BIMA and £12 717 (£9719) for SIMA (mean cost difference £1122, 95% CI £407 to £1838, p=0.002). No tests for interaction between subgroups and treatment allocation were significant. CONCLUSIONS: At 12 months from randomisation, mean costs were approximately 9% higher in BIMA than SIMA patients, primarily due to longer time in theatre and in-hospital stay, and slightly higher costs related to sternal wound problems during follow-up. Follow-up to the primary trial endpoint of 10 years will reveal whether longer-term differences emerge in graft patency or in overall survival. TRIAL REGISTRATION NUMBER: Controlled-trials.com (ISRCTN46552265).

Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, intravenous, and intraperitoneal administration of cyclophosphamide.

OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4-hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, IV, and IP administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive cyclophosphamide (200 mg/m2) via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration-versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients.

Clinical effectiveness and cost-effectiveness of open and arthroscopic rotator cuff repair [the UK Rotator Cuff Surgery (UKUFF) randomised trial].

BACKGROUND: Uncertainty exists regarding the best management of patients with degenerative tears of the rotator cuff. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of arthroscopic and open rotator cuff repair in patients aged ≥ 50 years with degenerative rotator cuff tendon tears. DESIGN: Two parallel-group randomised controlled trial. SETTING: Nineteen teaching and district general hospitals in the UK. PARTICIPANTS: Patients (n = 273) aged ≥ 50 years with degenerative rotator cuff tendon tears. INTERVENTIONS: Arthroscopic surgery and open rotator cuff repair, with surgeons using their usual and preferred method of arthroscopic or open repair. Follow-up was by telephone questionnaire at 2 and 8 weeks after surgery and by postal questionnaire at 8, 12 and 24 months after randomisation. MAIN OUTCOME MEASURES: The Oxford Shoulder Score (OSS) at 24 months was the primary outcome measure. Magnetic resonance imaging evaluation of the shoulder was made at 12 months after surgery to assess the integrity of the repair. RESULTS: The mean OSS improved from 26.3 [standard deviation (SD) 8.2] at baseline to 41.7 (SD 7.9) at 24 months for arthroscopic surgery and from 25.0 (SD 8.0) at baseline to 41.5 (SD 7.9) at 24 months for open surgery. When effect sizes are shown for the intervention, a negative sign indicates that an open procedure is favoured. For the intention-to-treat analysis, there was no statistical difference between the groups, the difference in OSS score at 24 months was -0.76 [95% confidence interval (CI) -2.75 to 1.22; p = 0.452] and the CI excluded the predetermined clinically important difference in the OSS of 3 points. There was also no statistical difference when the groups were compared per protocol (difference in OSS score -0.46, 95% CI -5.30 to 4.39; p = 0.854). The questionnaire response rate was > 86%. At 8 months, 77% of participants reported that shoulder problems were much or slightly better, and at 24 months this increased to 85%. There were no significant differences in mean cost between the arthroscopic group and the open repair group for any of the component resource-use categories, nor for the total follow-up costs at 24 months. The overall treatment cost at 2 years was £2567 (SD £176) for arthroscopic surgery and £2699 (SD £149) for open surgery, according to intention-to-treat analysis. For the per-protocol analysis there was a significant difference in total initial procedure-related costs between the arthroscopic group and the open repair group, with arthroscopic repair being more costly by £371 (95% CI £135 to £607). Total quality-adjusted life-years accrued at 24 months averaged 1.34 (SD 0.05) in the arthroscopic repair group and 1.35 (SD 0.05) in the open repair group, a non-significant difference of 0.01 (95% CI -0.11 to 0.10). The rate of re-tear was not significantly different across the randomised groups (46.4% and 38.6% for arthroscopic and open surgery, respectively). The participants with tears that were impossible to repair had the lowest OSSs, the participants with re-tears had slightly higher OSSs and the participants with healed repairs had the most improved OSSs. These findings were the same when analysed per protocol. CONCLUSION: In patients aged > 50 years with a degenerative rotator cuff tear there is no difference in clinical effectiveness or cost-effectiveness between open repair and arthroscopic repair at 2 years for the primary outcome (OSS) and all other prespecified secondary outcomes. Future work should explore new methods to improve tendon healing and reduce the high rate of re-tears observed in this trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97804283. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 80. See the NIHR Journals Library website for further project information.