Clinical and cost-effectiveness of PCF versus ACD in the treatment of cervical brachialgia (FORVAD trial).

BACKGROUND: Cervical radiculopathy occurs when a nerve root is compressed in the spine, if symptoms fail to resolve after 6 weeks surgery may be indicated. Anterior Cervical Discectomy (ACD) is the commonest procedure, Posterior Cervical Foraminotomy (PCF) is an alternative that avoids the risk of damage to anterior neck structures. This prospective, Phase III, UK multicentre, open, individually randomised controlled trial was performed to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post-surgery. METHOD: Following consent to participate and collection of baseline data, subjects with cervical brachialgia were randomised to ACD or PCF in a 1:1 ratio on the day of surgery. Clinical outcomes were assessed on day 1 and patient reported outcomes on day 1 and weeks 6, 12, 26, 39 and 52 post-operation. A total of 252 participants were planned to be randomised. Statistical analysis was limited to descriptive statistics. Health economic outcomes were also described. RESULTS: The trial was closed early (n = 23). Compared to baseline, the median (interquartile range (IQR)) NDI score at 52 weeks reduced from 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group and increased from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. ACD may be associated with more swallowing, voice and other complications and was more expensive; neck and arm pain scores were similar. CONCLUSIONS: The trial was closed early, therefore no definitive conclusions on clinical or cost-effectiveness could be made.

Revising the Suspected-Cancer Guidelines: Impacts on Patients' Primary Care Contacts and Costs.

OBJECTIVES: This study aimed to explore the impact of revising suspected-cancer referral guidelines on primary care contacts and costs. METHODS: Participants had incident cancer (colorectal, n = 2000; ovary, n = 763; and pancreas, n = 597) codes in the Clinical Practice Research Datalink or England cancer registry. Difference-in-differences analyses explored guideline impacts on contact days and nonzero costs between the first cancer feature and diagnosis. Participants were controls ("old National Institute for Health and Care Excellence [NICE]") or "new NICE" if their index feature was introduced during guideline revision. Model assumptions were inspected visually and by falsification tests. Sensitivity analyses reclassified participants who subsequently presented with features in the original guidelines as "old NICE." For colorectal cancer, sensitivity analysis (n = 3481) adjusted for multimorbidity burden. RESULTS: Median contact days and costs were, respectively, 4 (interquartile range [IQR] 2-7) and £117.69 (IQR £53.23-£206.65) for colorectal, 5 (IQR 3-9) and £156.92 (IQR £78.46-£272.29) for ovary, and 7 (IQR 4-13) and £230.64 (IQR £120.78-£408.34) for pancreas. Revising ovary guidelines may have decreased contact days (incidence rate ratio [IRR] 0.74; 95% confidence interval 0.55-1.00; P = .05) with unchanged costs, but parallel trends assumptions were violated. Costs decreased by 13% (equivalent to -£28.05, -£50.43 to -£5.67) after colorectal guidance revision but only in sensitivity analyses adjusting for multimorbidity. Contact days and costs remained unchanged after pancreas guidance revision. CONCLUSIONS: The main analyses of symptomatic patients suggested that prediagnosis primary care costs remained unchanged after guidance revision for pancreatic cancer. For colorectal cancer, contact days and costs decreased in analyses adjusting for multimorbidity. Revising ovarian cancer guidelines may have decreased primary care contact days but not costs, suggesting increased resource-use intensity; nevertheless, there is evidence of confounding.

Analysis of 18F-Sodium Fluoride Positron Emission Tomography Signal Sources in Atherosclerotic Minipigs Shows Specific Binding of 18F-Sodium Fluoride to Plaque Calcifications.

Objective: 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and Results: Gain-of-function PCSK9D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications. Conclusions: 18F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.

New horizons in evidence-based care for older people: individual participant data meta-analysis.

Evidence-based decisions on clinical and cost-effectiveness of interventions are ideally informed by meta-analyses of intervention trial data. However, when undertaken, such meta-analyses in ageing research have typically been conducted using standard methods whereby summary (aggregate) data are extracted from published trial reports. Although meta-analysis of aggregate data can provide useful insights into the average effect of interventions within a selected trial population, it has limitations regarding robust conclusions on which subgroups of people stand to gain the greatest benefit from an intervention or are at risk of experiencing harm. Future evidence synthesis using individual participant data from ageing research trials for meta-analysis could transform understanding of the effectiveness of interventions for older people, supporting evidence-based and sustainable commissioning. A major advantage of individual participant data meta-analysis (IPDMA) is that it enables examination of characteristics that predict treatment effects, such as frailty, disability, cognitive impairment, ethnicity, gender and other wider determinants of health. Key challenges of IPDMA relate to the complexity and resources needed for obtaining, managing and preparing datasets, requiring a meticulous approach involving experienced researchers, frequently with expertise in designing and analysing clinical trials. In anticipation of future IPDMA work in ageing research, we are establishing an international Ageing Research Trialists collective, to bring together trialists with a common focus on transforming care for older people as a shared ambition across nations.

Accounting for Heterogeneity in Resource Allocation Decisions: Methods and Practice in UK Cancer Technology Appraisals.

OBJECTIVES: The availability of novel, more efficacious and expensive cancer therapies is increasing, resulting in significant treatment effect heterogeneity and complicated treatment and disease pathways. The aim of this study is to review the extent to which UK cancer technology appraisals (TAs) consider the impact of patient and treatment effect heterogeneity. METHODS: A systematic search of National Institute for Health and Care Excellence TAs of colorectal, lung and ovarian cancer was undertaken for the period up to April 2020. For each TA, the pivotal clinical studies and economic evaluations were reviewed for considerations of patient and treatment effect heterogeneity. The study critically reviews the use of subgroup analysis and real-world translation in economic evaluations, alongside specific attributes of the economic modeling framework. RESULTS: The search identified 49 TAs including 49 economic models. In total, 804 subgroup analyses were reported across 69 clinical studies. The most common stratification factors were age, gender, and Eastern Cooperative Oncology Group performance score, with 15% (119 of 804) of analyses demonstrating significantly different clinical outcomes to the main population; economic subgroup analyses were undertaken in only 17 TAs. All economic models were cohort-level with the majority described as partitioned survival models (39) or Markov/semi-Markov models. The impact of real-world heterogeneity on disease progression estimates was only explored in 2 models. CONCLUSION: The ability of current modeling approaches to capture patient and treatment effect heterogeneity is constrained by their limited flexibility and simplistic nature. This study highlights a need for the use of more sophisticated modeling methods that enable greater consideration of real-world heterogeneity.

Quantitative assessment of myocardial blood flow and extracellular volume fraction using 68Ga-DOTA-PET: A feasibility and validation study in large animals.

BACKGROUND: Here we evaluated the feasibility of PET with Gallium-68 (68Ga)-labeled DOTA for non-invasive assessment of myocardial blood flow (MBF) and extracellular volume fraction (ECV) in a pig model of myocardial infarction. We also aimed to validate MBF measurements using microspheres as a gold standard in healthy pigs. METHODS: 8 healthy pigs underwent three sequential 68Ga-DOTA-PET/CT scans at rest and during pharmacological stress with simultaneous injection of fluorescent microspheres to validate MBF measurements. Myocardial infarction was induced in 5 additional pigs, which underwent 68Ga-DOTA-PET/CT examinations 7-days after reperfusion. Dynamic PET images were reconstructed and fitted to obtain MBF and ECV parametric maps. RESULTS: MBF assessed with 68Ga-DOTA-PET showed good correlation (y = 0.96x + 0.11, r = 0.91) with that measured with microspheres. MBF values obtained with 68Ga-DOTA-PET in the infarcted area (LAD, left anterior descendant) were significantly reduced in comparison to remote ones LCX (left circumflex artery, P < 0.0001) and RCA (right coronary artery, P < 0.0001). ECV increased in the infarcted area (P < 0.0001). CONCLUSION: 68Ga-DOTA-PET allowed non-invasive assessment of MBF and ECV in pigs with myocardial infarction and under rest-stress conditions. This technique could provide wide access to quantitative measurement of both MBF and ECV with PET imaging.

The heterogeneous causal effects of neonatal care: a model of endogenous demand for multiple treatment options based on geographical access to care.

Neonatal units in the UK are organised into three levels, from highest Neonatal Intensive Care Unit (NICU), to Local Neonatal Unit (LNU) to lowest Special Care Unit (SCU). We model the endogenous treatment selection of neonatal care unit of birth to estimate the average and marginal treatment effects of different neonatal designations on infant mortality, length of stay and hospital costs. We use prognostic factors, survival and hospital care use data on all preterm births in England for 2014-2015, supplemented by national reimbursement tariffs and instrumental variables of travel time from a geographic information system. The data were consistent with a model of demand for preterm birth care driven by physical access. In-hospital mortality of infants born before 32 weeks was 8.5% overall, and 1.2 (95% CI: -0.7, 3.2) percentage points lower for live births in hospitals with NICU or SCU compared to those with an LNU according to instrumental variable estimates. We find imprecise differences in average total hospital costs by unit designation, with positive unobserved selection of those with higher unexplained absolute and incremental costs into NICU. Our results suggest a limited scope for improvement in infant mortality by increasing in-utero transfers based on unit designation alone.

Predicting incident delirium diagnoses using data from primary-care electronic health records.

IMPORTANCE: risk factors for delirium in hospital inpatients are well established, but less is known about whether delirium occurring in the community or during an emergency admission to hospital care might be predicted from routine primary-care records. OBJECTIVES: identify risk factors in primary-care electronic health records (PC-EHR) predictive of delirium occurring in the community or recorded in the initial episode in emergency hospitalisation. Test predictive performance against the cumulative frailty index. DESIGN: Stage 1: case-control; Stages 2 and 3: retrospective cohort. SETTING: clinical practice research datalink: PC-EHR linked to hospital discharge data from England. SUBJECTS: Stage 1: 17,286 patients with delirium aged ≥60 years plus 85,607 controls. Stages 2 and 3: patients ≥ 60 years (n = 429,548 in 2015), split into calibration and validation groups. METHODS: Stage 1: logistic regression to identify associations of 110 candidate risk measures with delirium. Stage 2: calibrating risk factor weights. Stage 3: validation in independent sample using area under the curve (AUC) receiver operating characteristic. RESULTS: fifty-five risk factors were predictive, in domains including: cognitive impairment or mental illness, psychoactive drugs, frailty, infection, hyponatraemia and anticholinergic drugs. The derived model predicted 1-year incident delirium (AUC = 0.867, 0.852:0.881) and mortality (AUC = 0.846, 0.842:0.853), outperforming the frailty index (AUC = 0.761, 0.740:0.782). Individuals with the highest 10% of predicted delirium risk accounted for 55% of incident delirium over 1 year. CONCLUSIONS: a risk factor model for delirium using data in PC-EHR performed well, identifying individuals at risk of new onsets of delirium. This model has potential for supporting preventive interventions.

Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation.

BACKGROUND: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. METHODS: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used. RESULTS: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used. CONCLUSIONS: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources.

Micro-costing analysis of guideline-based treatment by direct-acting agents: the real-life case of hepatitis C management in Brazil.

BACKGROUND: Eradication of hepatitis C virus (HCV) using direct-acting agents (DAA) has been associated with a financial burden to health authorities worldwide. We aimed to evaluate the guideline-based treatment costs by DAAs from the perspective of the Brazilian Ministry of Health (BMoH). METHODS: The activity based costing method was used to estimate the cost for monitoring/treatment of genotype-1 (GT1) HCV patients by the following strategies: peg-interferon (PEG-IFN)/ribavirin (RBV) for 48 weeks, PEG-IFN/RBV plus boceprevir (BOC) or telaprevir (TEL) for 48 weeks, and sofosbuvir (SOF) plus daclastavir (DCV) or simeprevir (SIM) for 12 weeks. Costs were reported in United States Dollars without (US$) and with adjustment for purchasing power parity (PPP$). Drug costs were collected at the National Database of Health Prices and an overview of the literature was performed to assess effectiveness of SOF/DCV and SOF/SIM regimens in real-world cohorts. RESULTS: Treatment costs of GT1-HCV patients were PPP$ 43,176.28 (US$ 24,020.16) for PEG-IFN/RBV, PPP$ 71,196.03 (US$ 39,578.23) for PEG-IFN/RBV/BOC and PPP$ 86,250.33 (US$ 47,946.92) for PEG-IFN/RBV/TEL. Treatment by all-oral interferon-free regimens were the less expensive approach: PPP$ 19,761.72 (US$ 10,985.90) for SOF/DCV and PPP$ 21,590.91 (US$ 12,002.75) for SOF/SIM. The overview reported HCV eradication in up to 98% for SOF/DCV and 96% for SOF/SIM. CONCLUSION: Strategies with all oral interferon-free might lead to lower costs for management of GT1-HCV patients compared to IFN-based regimens in Brazil. This occurred mainly because of high discounts over international DAA prices due to negotiation between BMoH and pharmaceutical industries.

Stated preferences for anti-malarial drug characteristics in Zomba, a malaria endemic area of Malawi.

BACKGROUND: The evidence on determinants of individuals' choices for anti-malarial drug treatments is scarce. This study sought to measure the strength of preference for adult antimalarial drug treatment attributes of heads of urban, rural and peri-urban households in a resource-limited malaria-endemic area of sub-Saharan Africa. METHODS: Discrete choice experiments were conducted with 508 heads of household interviewed face-to-face for a household population survey of health-seeking behavior in Zomba District, Malawi. The interviews were held in Chichewa and the choice experiment questions were presented with cartoon aids. The anti-malarial drug attributes included in the stated preference experiment were: speed of fever resolution, side effects (pruritus) risk, protection (duration of prophylactic effect), price, duration of treatment course and recommendation by a health professional. Sixteen treatment profiles from a fractional factorial design by orthogonal array were paired into choice scenarios, and scenarios were randomly assigned to participants so that each participant was presented with a series of eight pairwise choice scenarios. Respondents had the option to state indifference between the two profiles or decline to choose. Data were analysed in a mixed logit model, with normally distributed coefficients for all six attributes. RESULTS: The sex ratio was balanced in urban areas, whereas 63% of participants in rural areas were male. The proportion of individuals with no education was considerably higher in the rural group (25%) than in the urban (5%) and peri-urban (6%) groups. All attributes investigated had the expected influence, and traded-off in most respondents' choices. There were heterogeneous effects of price, pruritus risk, treatment recommendation by a professional, and duration of prophylaxis across respondents, only partly explained by their differences in education, household per capita expenditure, sex and age. Individuals' demand elasticity (simulated median, inter-quartile range) was highest (most responsive) to speed of symptom resolution (0.88, 0.80-0.89) and pruritus risk (0.25, 0.08-0.62). CONCLUSIONS: Most adult antimalarial users are willing to use treatments without recommendation from health professional, and may be influenced by price. Future studies should investigate the magnitude of differences in price and treatment attribute sensitivity between adult anti-malarial drug users in rural, peri-urban and urban areas in order to determine optimal price subsidies.

Stereotactic radiosurgery for nonfunctioning pituitary tumor: A multicenter study of new pituitary hormone deficiency.

BACKGROUND: Stereotactic radiosurgery (SRS) is used to treat recurrent or residual nonfunctioning pituitary neuroendocrine tumors (NFPA). The objective of the study was to assess imaging and development of new pituitary hormone deficiency. METHODS: Patients treated with single-session SRS for a NFPA were included in this retrospective, multicenter study. Tumor control and new pituitary dysfunction were evaluated using Cox analysis and Kaplan-Meier curves. RESULTS: A total of 869 patients (male 476 [54.8%], median age at SRS 52.5 years [Interquartile range (IQR): 18.9]) were treated using a median margin dose of 14Gy (IQR: 4) for a median tumor volume of 3.4 cc (IQR: 4.3). With a median radiological follow-up of 3.7 years (IQR: 4.8), volumetric tumor reduction occurred in 451 patients (51.9%), stability in 364 (41.9%) and 54 patients (6.2%) showed tumor progression.The probability of tumor control was 95.5% (95% Confidence Interval [CI]: 93.8-97.3) and 88.8% (95%CI: 85.2-92.5) at 5 and 10 years, respectively. A margin dose >14 Gy was associated with tumor control (Hazard Ratio [HR]:0.33, 95% CI: 0.18-0.60, P < 0.001). The probability of new hypopituitarism was 9.9% (95% CI: 7.3-12.5) and 15.3% (95% CI: 11-19.4) at 5 and 10 years, respectively. A maximum point dose >10 Gy in the pituitary stalk was associated with new pituitary hormone deficiency (HR: 3.47, 95% CI: 1.95-6.19). The cumulative probability of new cortisol, thyroid, gonadotroph, and growth hormone deficiency was 8% (95% CI: 3.9-11.9), 8.3% (95% CI: 3.9-12.5), 3.5% (95% CI: 1.7-5.2), and 4.7% (95% CI: 1.9-7.4), respectively at 10 years. CONCLUSIONS: SRS provides long-term tumor control with a 15.3% risk of hypopituitarism at 10 years.

Long-term radiographic and endocrinological outcomes of stereotactic radiosurgery for recurrent or residual nonfunctioning pituitary adenomas.

OBJECTIVE: Stereotactic radiosurgery (SRS) is used for the treatment of residual/recurrent nonfunctional pituitary adenoma (NFPA). The aim of this study was to evaluate the factors related to long-term tumor control and delayed endocrinopathies following SRS. METHODS: This retrospective, multicenter study included patients with recurrent/residual NFPA treated with single-fraction SRS; they were then divided into two arms. The first arm included patients with at least 5 years of radiographic follow-up and all patients with local tumor progression. The second arm included patients with at least 5 years of endocrinological follow-up and all patients who developed endocrinopathy. Study endpoints were tumor control and new or worsening hypopituitarism after SRS and were analyzed using Cox regression and Kaplan-Meier methodology. RESULTS: There were 360 patients in the tumor control arm (median age 52.7 [IQR 42.9-61] years, 193 [53.6%] males) and 351 patients in the hypopituitarism arm (median age 52.5 [IQR 43-61] years, 186 [53.0%] males). The median follow-up in the tumor control evaluation group was 7.95 (IQR 5.7-10.5) years. Tumor control rates at 5, 8, 10, and 15 years were 93% (95% CI 90%-95%), 87% (95% CI 83%-91%), 86% (95% CI 82%-90%), and 69% (95% CI 59%-81%), respectively. The median follow-up in the endocrinopathy evaluation group was 8 (IQR 5.9-10.7) years. Pituitary function preservation rates at 5, 8, 10, and 15 years were 83% (95% CI 80%-87%), 81% (95% CI 77%-85%), 78% (95% CI 74%-83%), and 71% (95% CI 63%-79%), respectively. A margin dose > 15 Gy (HR 0.8, 95% CI 0.7-0.9; p < 0.001) and a delay from last resection to SRS > 1 year (HR 0.9, 95% CI 0.7-0.9; p = 0.04) were significant factors related to tumor control in multivariable analysis. A maximum dose to the pituitary stalk ≤ 10 Gy (HR 1.1, 95% CI 1.09-1.2; p < 0.001) was associated with pituitary function preservation. New visual deficits after SRS occurred in 7 (1.94%) patients in the tumor control group and 8 (2.3%) patients in the endocrinopathy group. Other new cranial nerve deficits post-SRS occurred in 4 of 160 patients with data in the tumor control group and 3 of 140 patients with data in the endocrinopathy group. CONCLUSIONS: SRS affords favorable and durable tumor control for the vast majority of NFPAs. Post-SRS hypopituitarism occurs in a minority of patients, but this risk increases with time and warrants long-term follow-up.

Cost-effectiveness analysis of early versus late total hip replacement in Italy.

OBJECTIVE: To assess the cost-effectiveness of early primary total hip replacement (THR) for functionally independent older adult patients with osteoarthritis (OA) versus 1) nonsurgical therapy followed by THR once the patient has progressed to a functionally dependent state ("delayed THR") and 2) nonsurgical therapy alone ('medical therapy'), from the Italian National Health Service perspective. METHODS: Individual patient data and evidence from published literature on disease progression, economic costs and THR outcomes in OA, including utilities, perioperative mortality rates, prosthesis survival, and costs of prostheses, THR, rehabilitation, follow-up, revision, and nonsurgical management, combined with population life tables, were synthesized in a Markov model of OA. The model represents the lifetime experience of a patient cohort following their treatment choice, discounting costs and benefits (quality-adjusted life-years) at 3% annually. RESULTS: At age 65 years, the incremental cost per quality-adjusted life-year of THR over delayed THR was €987 in men and €466 in women; the figures for delayed THR versus medical therapy were €463 and €82, respectively. Among 80-year-olds, early THR is (extended) dominant. With gradual utility loss after primary THR, delaying surgery may be more appealing in women than in men in their 50s, because longer female life expectancy implies longer latter periods of low health-related quality of life (HRQOL) with early THR. CONCLUSIONS: THR is cost-effective. Patients' HRQOL benefits forgone with delayed THR are worth more than the costs it saves to the Italian National Health Service. This analysis might help to explain women's consistently lower HRQOL by the time of primary operation.

Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression.

The retinoid X receptor alpha (RXRalpha) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRalpha regulates the transcription of the chemokines Ccl6 and Ccl9 in macrophages independently of heterodimeric partners. Mice lacking RXRalpha in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRalpha plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.

Treatment of tibial bone defects: pilot analysis of direct medical costs between distraction osteogenesis with an Ilizarov frame and the Masquelet technique.

PURPOSE: The cost implications of limb reconstruction techniques have not been adequately investigated. Aim of this pilot study was to compare the direct medical cost of tibial bone defects managed with distraction osteogenesis-Ilizarov method (ILF), or with Masquelet technique (MIF). METHODS: Data of 20 random patients treated in a single centre were analysed. Inclusion criteria included acute tibial defects, or post-debridement of nonunions with complete follow-up and successful union. The endpoint of clinical efficacy was the time-to-defect union. Comparisons were made between equally sized subgroups (ILF vs. MIF). RESULTS: The average defect length was 5.6 cm (2.6-9.6 cm). The overall cost of 20 cases reached £452,974 (mean £22,339, range £13,459-£36,274). Statistically significant differences favoring the MIF were found regarding the average time-to-union; number of surgeries, of admissions and follow-up visits, as well as the mean intraoperative cost (£8857 vs. £14,087). These differences lead to significant differences of the mean cost of the overall treatment (MIF £18,131 vs. ILF £26,126). Power analysis based on these data indicated that 35 patients on each group would allow detection of a 25% difference, with an alpha value of 0.05 and probability (power) of 0.9. CONCLUSIONS: The results and analysis presented highlight factors affecting the high financial burden, even in a best-case scenario, this type of surgery entails. Larger pivotal studies should follow to improve the cost efficiency of clinical practice.

Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial.

INTRODUCTION: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing. METHODS AND ANALYSIS: The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation. ETHICS AND DISSEMINATION: This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal. TRIAL REGISTRATION: ISRCTN20579216.

Posterior cervical foraminotomy versus anterior cervical discectomy for Cervical Brachialgia: the FORVAD RCT.

Background: Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective: The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design: This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting: National Health Service trusts. Participants: Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions: Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures: The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow-Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results: The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0-62.0 weeks) and 25.3 weeks (interquartile range 20.0-42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0-44.0 weeks) and 45.0 weeks (interquartile range 20.0-57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow-Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale - Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale - Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions: The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration: This trial is registered as ISRCTN10133661. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.

Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients' quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future.

Determinants of demand for total hip and knee arthroplasty: a systematic literature review.

BACKGROUND: Documented age, gender, race and socio-economic disparities in total joint arthroplasty (TJA), suggest that those who need the surgery may not receive it, and present a challenge to explain the causes of unmet need. It is not clear whether doctors limit treatment opportunities to patients, nor is it known the effect that patient beliefs and expectations about the operation, including their paid work status and retirement plans, have on the decision to undergo TJA. Identifying socio-economic and other determinants of demand would inform the design of effective and efficient health policy. This review was conducted to identify the factors that lead patients in need to undergo TJA. METHODS: An electronic search of the Embase and Medline (Ovid) bibliographic databases conducted in September 2011 identified studies in the English language that reported on factors driving patients in need of hip or knee replacement to undergo surgery. The review included reports of elective surgery rates in eligible patients or, controlling for disease severity, in general subjects, and stated clinical experts' and patients' opinions on suitability for or willingness to undergo TJA. Quantitative and qualitative studies were reviewed, but quantitative studies involving fewer than 20 subjects were excluded. The quality of individual studies was assessed on the basis of study design (i.e., prospective versus retrospective), reporting of attrition, adjustment for and report of confounding effects, and reported measures of need (self-reported versus doctor-assessed). Reported estimates of effect on the probability of surgery from analyses adjusting for confounders were summarised in narrative form and synthesised in odds ratio (OR) forest plots for individual determinants. RESULTS: The review included 26 quantitative studies-23 on individuals' decisions or views on having the operation and three about health professionals' opinions-and 10 qualitative studies. Ethnic and racial disparities in TJA use are associated with socio-economic access factors and expectations about the process and outcomes of surgery. In the United States, health insurance coverage affects demand, including that from the Medicare population, for whom having supplemental Medicaid coverage increases the likelihood of undergoing TJA. Patients with post-secondary education are more likely to demand hip or knee surgery than those without it (range of OR 0.87-2.38). Women are as willing to undergo surgery as men, but they are less likely to be offered surgery by specialists than men with the same need. There is considerable variation in patient demand with age, with distinct patterns for hip and knee. Paid employment appears to increase the chances of undergoing surgery, but no study was found that investigated the relationship between retirement plans and demand for TJA. There is evidence of substantial geographical variation in access to joint replacement within the territory covered by a public national health system, which is unlikely to be explained by differences in preference or unmeasured need alone. The literature tends to focus on associations, rather than testing of causal relationships, and is insufficient to assess the relative importance of determinants. CONCLUSIONS: Patients' use of hip and knee replacement is a function of their socio-economic circumstances, which reinforce disparities by gender and race originating in the doctor-patient interaction. Willingness to undergo surgery declines steeply after the age of retirement, at the time some eligible patients may lower their expectations of health status achievement. There is some evidence that paid employment independently increases the likelihood of operation. The relative contribution of variations in surgical decision making to differential access across regions within countries deserves further research that controls for clinical need and patient lifestyle preferences, including retirement decisions. Evidence on this question will become increasingly relevant for service planning and policy design in societies with ageing populations.

The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome.

The CD5 lymphocyte surface receptor is a group B member of the ancient and highly conserved scavenger receptor cysteine-rich superfamily. CD5 is expressed on mature T and B1a cells, where it is known to modulate lymphocyte activation and/or differentiation processes. Recently, the interaction of a few group B SRCR members (CD6, Spalpha, and DMBT1) with conserved microbial structures has been reported. Protein binding assays presented herein indicate that the CD5 ectodomain binds to and aggregates fungal cells (Schizosaccharomyces pombe, Candida albicans, and Cryptococcus neoformans) but not to Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus) bacteria. Accordingly, the CD5 ectodomain binds to zymosan but not to purified bacterial cell wall constituents (LPS, lipotheicoic acid, or peptidoglycan), and such binding is specifically competed by beta-glucan but not by mannan. The K(d) of the rshCD5/(1-->3)-beta-d-glucan phosphate interaction is 3.7 +/- 0.2 nM as calculated from tryptophan fluorescence data analysis of free and bound rshCD5. Moreover, zymosan binds to membrane-bound CD5, and this induces both MAPK activation and cytokine release. In vivo validation of the fungal binding properties of the CD5 ectodomain is deduced from its protective effect in a mouse model of zymosan-induced septic shock-like syndrome. In conclusion, the present results indicate that the CD5 lymphocyte receptor may sense the presence of conserved fungal components [namely, (1-->3)-beta-d-glucans] and support the therapeutic potential of soluble CD5 forms in fungal sepsis.