Alginates for Protection Against Pepsin-Acid Induced Aerodigestive Epithelial Barrier Disruption.

OBJECTIVE: Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are chronic conditions caused by backflow of gastric and duodenal contents into the esophagus and proximal aerodigestive tract, respectively. Mucosal barrier dysfunction resultant from the synergistic actions of chemical injury and the mucosal inflammatory response during reflux contributes to symptom perception. Alginates effectively treat symptoms of mild to moderate GERD and have recently shown benefit for LPR. In addition to forming a "raft" over gastric contents to reduce acidic reflux episodes, alginates have been found to bind the esophageal mucosa thereby preserving functional barrier integrity measured by transepithelial electrical resistance. The aim of this study was to further examine the topical protective capacity of alginate-based Gaviscon Advance (GA) and Double Action (GDA) against pepsin-acid mediated aerodigestive epithelial barrier dysfunction in vitro. STUDY DESIGN: Translational. METHODS: Immortalized human esophageal and vocal cord epithelial cells cultured in transwells were pretreated with liquid formula GA, GDA, matched viscous placebo solution, or saline (control), then treated for 1 h with saline, acid (pH 3-6) or pepsin (0.1-1 mg/ml) at pH 3-6. Endpoint measure was taken of horseradish peroxidase (HRP) allowed to diffuse across monolayers for 2 h. RESULTS: Pepsin (0.1-1 mg/ml) at pH 3-6 increased HRP flux through cultures pretreated with saline or placebo (p < 0.05); acid alone did not. GA and GDA prevented barrier dysfunction. CONCLUSIONS: GA and GDA preserved epithelial barrier function during pepsin-acid insult better than placebo suggesting that protection was due to alginate. These data support topical protection as a therapeutic approach to GERD and LPR. Laryngoscope, 132:2327-2334, 2022.

Using specialist screening practitioners (SSPs) to increase uptake of bowel scope (flexible sigmoidoscopy) screening: results of a feasibility single-stage phase II randomised trial.

OBJECTIVE: To determine the feasibility of specialist screening practitioners (SSPs) offering patient navigation (PN) to facilitate uptake of bowel scope screening (BSS) among patients who do not confirm or attend their appointment. DESIGN: A single-stage phase II trial. SETTING: South Tyneside District Hospital, Tyne and Wear, England, UK. PARTICIPANTS: Individuals invited for BSS at South Tyneside District Hospital during the 6-month recruitment period were invited to participate in the study. INTERVENTION: Consenting individuals were randomly assigned to either the PN intervention or usual care group in a 4:1 ratio. The intervention involved BSS non-attenders receiving a phone call from an SSP to elicit their reasons for non-attendance and offer educational, practical and emotional support as required. If requested by the patient, another BSS appointment was then scheduled. PRIMARY OUTCOME MEASURE: The number of non-attenders in the intervention group who were navigated and then rebooked and attended their new BSS appointment. SECONDARY OUTCOME MEASURES: Barriers to BSS attendance, patient-reported outcomes including informed choice and satisfaction with BSS and the PN intervention, reasons for study non-participation, SSPs' evaluation of the PN process and a cost analysis. RESULTS: Of those invited to take part (n=1050), 152 (14.5%) were randomised into the study: PN intervention=109; usual care=43. Most participants attended their BSS appointment (PN: 79.8%; control: 79.1%) leaving 22 eligible for PN: only two were successfully contacted. SSPs were confident in delivering PN, but were concerned that low BSS awareness and information overload may have deterred patients from taking part in the study. Difficulty contacting patients was reported as a burden to their workload. CONCLUSIONS: PN, as implemented, was not a feasible intervention to increase BSS uptake in South Tyneside. Interventions to increase BSS awareness may be better suited to this population. TRIAL REGISTRATION NUMBER: ISRCTN13314752; Results.

Cost-effectiveness of habit-based advice for weight control versus usual care in general practice in the Ten Top Tips (10TT) trial: economic evaluation based on a randomised controlled trial.

OBJECTIVE: Ten Top Tips (10TT) is a primary care-led behavioural intervention which aims to help adults reduce and manage their weight by following 10 weight loss tips. The intervention promotes habit formation to encourage long-term behavioural changes. The aim of this study was to estimate the cost-effectiveness of 10TT in general practice from the perspective of the UK National Health Service. DESIGN: An economic evaluation was conducted alongside an individually randomised controlled trial. SETTING: 14 general practitioner practices in England. PARTICIPANTS: All patients were aged ≥18 years, with body mass index ≥30 kg/m2. A total of 537 patients were recruited; 270 received the usual care offered by their practices and 267 received the 10TT intervention. OUTCOMES MEASURES: Health service use and quality-adjusted life years (QALYs) were measured over 2 years. Analysis was conducted in terms of incremental net monetary benefits (NMBs), using non-parametric bootstrapping and multiple imputation. RESULTS: Over a 2-year time horizon, the mean costs and QALYs per patient in the 10TT group were £1889 (95% CI £1522 to £2566) and 1.51 (95% CI 1.44 to 1.58). The mean costs and QALYs for usual care were £1925 (95% CI £1599 to £2251) and 1.51 (95% CI 1.45 to 1.57), respectively. This generated a mean cost difference of -£36 (95% CI -£512 to £441) and a mean QALY difference of 0.001 (95% CI -0.080 to 0.082). The incremental NMB for 10TT versus usual care was £49 (95% CI -£1709 to £1800) at a maximum willingness to pay for a QALY of £20 000. 10TT had a 52% probability of being cost-effective at this threshold. CONCLUSIONS: Costs and QALYs for 10TT were not significantly different from usual care and therefore 10TT is as cost-effective as usual care. There was no evidence to recommend nor advice against offering 10TT to obese patients in general practices based on cost-effectiveness considerations. TRIAL REGISTRATION NUMBER: ISRCTN16347068; Post-results.

The mesially impacted mandibular third molar: The incidence and consequences of distal cervical caries in the mandibular second molar.

AIMS: Distal Cervical Caries (DCC) of the mandibular second molar (Md2M) is primarily related to retained mesially impacted third molars (Md3M). Treatment of this condition indicates the removal of the Md3M and the restoration of the Md2M and, on occasions, the loss of the Md2M. The aim of this study was to determine the incidence, treatment outcomes for patients, and calculate costs related to Md2M DCC. METHODS: A review of 121 patients who had Md3M removed due to Md2M DCC was undertaken to determine the treatment outcomes for patients. The number of patients affected by DCC of Md2M was calculated from the incidence of DCC (15%) in a cohort of patients requiring Md3M removal (1100) and the annual number of patients undergoing third molar surgery in England. Direct costs were calculated using NHS and independent treatment tariffs and indirect costs from Office of National Statistics (ONS). RESULTS: It is estimated that 152,000 patients in England undergo third molar removal on an annual basis. Approximately 27,000 Md3M are removed annually due to DCC of the Md2M; costing £27 m to treat with additional costs of £28 m if dental implant replacement of the Md2M is included. Total cost for treating Md2M DCC: £55 m/annum. CONCLUSIONS: Treating Md2M DCC and its consequences is expensive for healthcare funders such as the NHS and for patients. Md2M DCC is avoidable if patients who are at risk have prophylactic Md3M removal. This would offer potential and substantial savings in the financial cost of treating an otherwise avoidable disease.

The economic costs of intrapartum care in Tower Hamlets: A comparison between the cost of birth in a freestanding midwifery unit and hospital for women at low risk of obstetric complications.

OBJECTIVE: to compare the economic costs of intrapartum maternity care in an inner city area for 'low risk' women opting to give birth in a freestanding midwifery unit compared with those who chose birth in hospital. DESIGN: micro-costing of health service resources used in the intrapartum care of mothers and their babies during the period between admission and discharge, data extracted from clinical notes. SETTING: the Barkantine Birth Centre, a freestanding midwifery unit and the Royal London Hospital's consultant-led obstetric unit, both run by the former Barts and the London NHS Trust in Tower Hamlets, a deprived inner city borough in east London, England, 2007-2010. PARTICIPANTS: maternity records of 333 women who were resident in Tower Hamlets and who satisfied the Trust's eligibility criteria for using the Birth Centre. Of these, 167 women started their intrapartum care at the Birth Centre and 166 started care at the Royal London Hospital. MEASUREMENTS AND FINDINGS: women who planned their birth at the Birth Centre experienced continuous intrapartum midwifery care, higher rates of spontaneous vaginal delivery, greater use of a birth pool, lower rates of epidural use, higher rates of established breastfeeding and a longer post-natal stay, compared with those who planned for care in the hospital. The total average cost per mother-baby dyad for care where mothers started their intrapartum care at the Birth Centre was £1296.23, approximately £850 per patient less than the average cost per mother and baby who received all their care at the Royal London Hospital. These costs reflect intrapartum throughput using bottom up costing per patient, from admission to discharge, including transfer, but excluding occupancy rates and the related running costs of the units. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the study showed that intrapartum throughput in the Birth Centre could be considered cost-minimising when compared to hospital. Modelling the financial viability of midwifery units at a local level is important because it can inform the appropriate provision of these services. This finding from this study contribute a local perspective and thus further weight to the evidence from the Birthplace Programme in support of freestanding midwifery unit care for women without obstetric complications.

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis.

BACKGROUND: Carotid artery stenting (CAS) is an alternative to carotid endarterectomy (CEA) for the treatment of carotid stenosis, but safety and long-term efficacy were uncertain. OBJECTIVE: To compare the risks, benefits and cost-effectiveness of CAS versus CEA for symptomatic carotid stenosis. DESIGN: International, multicentre, randomised controlled, open, prospective clinical trial. SETTING: Hospitals at 50 centres worldwide. PARTICIPANTS: Patients older than 40 years of age with symptomatic atheromatous carotid artery stenosis. INTERVENTIONS: Patients were randomly allocated stenting or endarterectomy using a computerised service and followed for up to 10 years. MAIN OUTCOME MEASURES: The primary outcome measure was the long-term rate of fatal or disabling stroke, analysed by intention to treat (ITT). Disability was assessed using the modified Rankin Scale (mRS). A cost-utility analysis estimating mean costs and quality-adjusted life-years (QALYs) was calculated over a 5-year time horizon. RESULTS: A total of 1713 patients were randomised but three withdrew consent immediately, leaving 1710 for ITT analysis (853 were assigned to stenting and 857 were assigned to endarterectomy). The incidence of stroke, death or procedural myocardial infarction (MI) within 120 days of treatment was 8.5% in the CAS group versus 5.2% in the CEA group (72 vs. 44 events) [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.16 to 2.45; p = 0.006]. In the analysis restricted to patients who completed stenting, age independently predicted the risk of stroke, death or MI within 30 days of CAS (relative risk increase 1.17% per 5 years of age, 95% CI 1.01% to 1.37%). Use of an open-cell stent conferred higher risk than a closed-cell stent (relative risk 1.92, 95% CI 1.11 to 3.33), but use of a cerebral protection device did not modify the risk. CAS was associated with a higher risk of stroke in patients with an age-related white-matter changes score of 7 or more (HR 2.98, 95% CI 1.29 to 6.93; p = 0.011). After completion of follow-up with a median of 4.2 years, the number of patients with fatal or disabling stroke in the CAS and CEA groups (52 vs. 49), and the cumulative 5-year risk did not differ significantly (6.4% vs. 6.5%) (HR 1.06, 95% CI 0.72 to 1.57; p = 0.776). Stroke of any severity was more frequent in the CAS group (15.2% vs. 9.4% in the CEA group) (HR 1.712, 95% CI 1.280 to 2.300; p < 0.001). There was no significant difference in long-term rates of severe carotid restenosis or occlusion (10.8% in the CAS group vs. 8.6% in the CEA group) (HR 1.25, 95% CI 0.89 to 1.75; p = 0.20). There was no difference in the distribution of mRS scores at 1-year, 5-year or final follow-up. There were no differences in costs or QALYs between the treatments. LIMITATIONS: Patients and investigators were not blinded to treatment allocation. Interventionists' experience of stenting was less than that of surgeons with endarterectomy. Data on costs of managing strokes were not collected. CONCLUSIONS: The functional outcome after stenting is similar to endarterectomy, but stenting is associated with a small increase in the risk of non-disabling stroke. The choice between stenting and endarterectomy should take into account the procedural risks related to individual patient characteristics. Future studies should include measurement of cognitive function, assessment of carotid plaque morphology and identification of clinical characteristics that determine benefit from revascularisation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25337470. 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. 20, No. 20. See the NIHR Journal Library website for further project information. Further funding was provided by the Medical Research Council, Stroke Association, Sanofi-Synthélabo and the European Union.

Cost-utility analysis of stenting versus endarterectomy in the International Carotid Stenting Study.

BACKGROUND: The International Carotid Stenting Study was a multicenter randomized trial in which patients with symptomatic carotid artery stenosis were randomly allocated to treatment by carotid stenting or endarterectomy. Economic evidence comparing these treatments is limited and inconsistent. AIMS: We compared the cost-effectiveness of stenting versus endarterectomy using International Carotid Stenting Study data. METHODS: We performed a cost-utility analysis estimating mean costs and quality-adjusted life years per patient for both treatments over a five-year time horizon based on resource use data and utility values collected in the trial. Costs of managing stroke events were estimated using individual patient data from a UK population-based study (Oxford Vascular Study). RESULTS: Mean costs per patient (95% CI) were US$10,477 ($9669 to $11,285) in the stenting group (N = 853) and $9669 ($8835 to $10,504) in the endarterectomy group (N = 857). There were no differences in mean quality-adjusted life years per patient (3.247 (3.160 to 3.333) and 3.228 (3.150 to 3.306), respectively). There were no differences in adjusted costs between groups (mean incremental costs for stenting versus endarterectomy $736 (95% CI -$353 to $1826)) or adjusted outcomes (mean quality-adjusted life years gained -0.010 (95% CI -0.117 to 0.097)). The incremental net monetary benefit for stenting versus endarterectomy was not significantly different from zero at the maximum willingness to pay for a quality-adjusted life year commonly used in the UK. Sensitivity analyses showed little uncertainty in these findings. CONCLUSIONS: Economic considerations should not affect whether patients with symptomatic carotid stenosis undergo stenting or endarterectomy.

A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: childhood outcomes at 5†years.

OBJECTIVE: We performed a randomised trial in very preterm, small for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). GM-CSF was associated with improved neonatal neutrophil counts, but no change in other neonatal or 2-year outcomes. As subtle benefits in outcome may not be ascertainable until school age we performed an outcome study at 5 years. PATIENTS AND METHODS: 280 babies born at 31 weeks of gestation or less and SGA were entered into the trial. Outcomes were assessed at 5 years to determine neurodevelopmental and general health status and educational attainment. RESULTS: We found no significant differences in cognitive, general health or educational outcomes between 83 of 106 (78%) surviving children in the GM-CSF arm compared with 81 of 110 (74%) in the control arm. Mean mental processing composite (equivalent to IQ) at 5 years were 94 (SD 16) compared with 95 (SD 15), respectively (difference in means -1 (95%CI -6 to 4), and similar proportions were in receipt of special educational needs support (41% vs 35%; risk ratio 1.2 (95% CI 0.8 to 1.9)). Performance on Kaufmann-ABC subscales and components of NEPSY were similar. The suggestion of worse respiratory outcomes in the GM-CSF group at 2 years was replicated at 5 years. CONCLUSIONS: The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse neurodevelopmental, general health or educational outcomes at 5 years. TRIAL REGISTRATION NUMBER: ISRCTN42553489.

A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.

OBJECTIVES: To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN: This was a pilot, open-label, three-arm prospective phase 1 study. METHODS: We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS: One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1ß - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1ß, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION: Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.

Monetary costs of agitation in older adults with Alzheimer's disease in the UK: prospective cohort study.

OBJECTIVE: While nearly half of all people with Alzheimer's disease (AD) have agitation symptoms every month, little is known about the costs of agitation in AD. We calculated the monetary costs associated with agitation in older adults with AD in the UK from a National Health Service and personal social services perspective. DESIGN: Prospective cohort study. SETTING: London and the South East Region of the UK (LASER-AD study). PARTICIPANTS: 224 people with AD recruited between July 2002 and January 2003 and followed up for 54 months. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was health and social care costs, including accommodation costs and costs of contacts with health and social care services. Agitation was assessed using the Neuropsychiatric Inventory (NPI) agitation score. RESULTS: After adjustment, health and social care costs varied significantly by agitation, from £29,000 over a 1 year period with no agitation symptoms (NPI agitation score=0) to £57,000 at the most severe levels of agitation (NPI agitation score=12; p=0.01). The mean excess cost associated with agitation per person with AD was £4091 a year, accounting for 12% of the health and social care costs of AD in our data, and equating to £2 billion a year across all people with AD in the UK. CONCLUSIONS: Agitation in people with AD represents a substantial monetary burden over and above the costs associated with cognitive impairment.

Understanding quality improvement at scale in general practice: a qualitative evaluation of a COPD improvement programme.

BACKGROUND: A growing body of knowledge exists to guide efforts to improve the organisation and delivery of health care, most of which is based on work carried out in hospitals. It is uncertain how transferable this knowledge is to primary care. AIM: To understand the enablers and constraints to implementing a large-scale quality improvement programme in general practice, designed to improve care for people with chronic obstructive pulmonary disease. DESIGN AND SETTING: A qualitative study of 189 general practices in a socioeconomically and ethnically-mixed, urban area in east London, UK. METHOD: Twelve semi-structured interviews were conducted with people leading the programme and 17 in-depth interviews with those participating in it. Participants were local health system leaders, clinicians, and managers. A theoretical framework derived from evidence-based guidance for improvement programmes was used to interpret the findings. A complex improvement intervention took place with social and technical elements including training and mentorship, guidance, analytical tools, and data feedback. RESULTS: Practice staff wanted to participate in and learn from well-designed collaborative improvement projects. Nevertheless, there were limitations in the capacities and capabilities of the workforce to undertake systematic improvement, significant problems with access to and the quality of data, and tensions between the narrative-based generalist orientation of many primary care clinicians and the quantitative single-disease orientation that has characterised much of the quality improvement movement to date. CONCLUSION: Improvement guidance derived largely from hospital-based studies is, for the most part, applicable to improvement efforts in primary care settings, although large-scale change in general practice presents some particular challenges. These need to be better understood and addressed if improvement initiatives are to be effective.

Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials.

BACKGROUND: Agitation in dementia is common, persistent and distressing and can lead to care breakdown. Medication is often ineffective and harmful. AIMS: To systematically review randomised controlled trial evidence regarding non-pharmacological interventions. Method We reviewed 33 studies fitting predetermined criteria, assessed their validity and calculated standardised effect sizes (SES). RESULTS: Person-centred care, communication skills training and adapted dementia care mapping decreased symptomatic and severe agitation in care homes immediately (SES range 0.3-1.8) and for up to 6 months afterwards (SES range 0.2-2.2). Activities and music therapy by protocol (SES range 0.5-0.6) decreased overall agitation and sensory intervention decreased clinically significant agitation immediately. Aromatherapy and light therapy did not demonstrate efficacy. CONCLUSIONS: There are evidence-based strategies for care homes. Future interventions should focus on consistent and long-term implementation through staff training. Further research is needed for people living in their own homes.

A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia.

BACKGROUND: Agitation is common, persistent and distressing in dementia and is linked with care breakdown. Psychotropic medication is often ineffective or harmful, but the evidence regarding non-pharmacological interventions is unclear. OBJECTIVES: We systematically reviewed and synthesised the evidence for clinical effectiveness and cost-effectiveness of non-pharmacological interventions for reducing agitation in dementia, considering dementia severity, the setting, the person with whom the intervention is implemented, whether the effects are immediate or longer term, and cost-effectiveness. DATA SOURCES: We searched twice using relevant search terms (9 August 2011 and 12 June 2012) in Web of Knowledge (incorporating MEDLINE); EMBASE; British Nursing Index; the Health Technology Assessment programme database; PsycINFO; NHS Evidence; System for Information on Grey Literature; The Stationery Office Official Documents website; The Stationery National Technical Information Service; Cumulative Index to Nursing and Allied Health Literature; and The Cochrane Library. We also searched Cochrane reviews of interventions for behaviour in dementia, included papers' references, and contacted authors about 'missed' studies. We included quantitative studies, evaluating non-pharmacological interventions for agitation in dementia, in all settings. REVIEW METHOD: We rated quality, prioritising higher-quality studies. We separated results by intervention type and agitation level. As we were unable to meta-analyse results except for light therapy, we present a qualitative evidence synthesis. In addition, we calculated standardised effect sizes (SESs) with available data, to compare heterogeneous interventions. In the health economic analysis, we reviewed economic studies, calculated the cost of effective interventions from the effectiveness review, calculated the incremental cost per unit improvement in agitation, used data from a cohort study to evaluate the relationship between health and social care costs and health-related quality of life (DEMQOL-Proxy-U scores) and developed a new cost-effectiveness model. RESULTS: We included 160 out of 1916 papers screened. Supervised person-centred care, communication skills (SES = -1.8 to -0.3) or modified dementia care mapping (DCM) with implementing plans (SES = -1.4 to -0.6) were all efficacious at reducing clinically significant agitation in care home residents, both immediately and up to 6 months afterwards. In care home residents, during interventions but not at follow-up, activities (SES = -0.8 to -0.6) and music therapy (SES = -0.8 to -0.5) by protocol reduced mean levels of agitation; sensory intervention (SES = -1.3 to -0.6) reduced mean and clinically significant symptoms. Advantages were not demonstrated with 'therapeutic touch' or individualised activity. Aromatherapy and light therapy did not show clinical effectiveness. Training family carers in behavioural or cognitive interventions did not decrease severe agitation. The few studies reporting activities of daily living or quality-of-life outcomes found no improvement, even when agitation had improved. We identified two health economic studies. Costs of interventions which significantly impacted on agitation were activities, £80-696; music therapy, £13-27; sensory interventions, £3-527; and training paid caregivers in person-centred care or communication skills with or without behavioural management training and DCM, £31-339. Among the 11 interventions that were evaluated using the Cohen-Mansfield Agitation Inventory (CMAI), the incremental cost per unit reduction in CMAI score ranged from £162 to £3480 for activities, £4 for music therapy, £24 to £143 for sensory interventions, and £6 to £62 for training paid caregivers in person-centred care or communication skills with or without behavioural management training and DCM. Health and social care costs ranged from around £7000 over 3 months in people without clinically significant agitation symptoms to around £15,000 at the most severe agitation levels. There is some evidence that DEMQOL-Proxy-U scores decline with Neuropsychiatric Inventory agitation scores. A multicomponent intervention in participants with mild to moderate dementia had a positive monetary net benefit and a 82.2% probability of being cost-effective at a maximum willingness to pay for a quality-adjusted life-year of £20,000 and a 83.18% probability at a value of £30,000. LIMITATIONS: Although there were some high-quality studies, there were only 33 reasonably sized (> 45 participants) randomised controlled trials, and lack of evidence means that we cannot comment on many interventions' effectiveness. There were no hospital studies and few studies in people's homes. More health economic data are needed. CONCLUSIONS: Person-centred care, communication skills and DCM (all with supervision), sensory therapy activities, and structured music therapies reduce agitation in care-home dementia residents. Future interventions should change care home culture through staff training and permanently implement evidence-based treatments and evaluate health economics. There is a need for further work on interventions for agitation in people with dementia living in their own homes. PROTOCOL REGISTRATION: The study was registered as PROSPERO no. CRD42011001370. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Economic evaluation of policy initiatives in the organisation and delivery of healthcare: a case study of gastroenterology endoscopy services.

BACKGROUND: Complex clinical interventions are increasingly subject to evaluation by randomised trial linked to economic evaluation. However evaluations of policy initiatives tend to eschew experimental designs in favour of interpretative perspectives which rarely allow the economic evaluation methods used in clinical trials. As evidence of the cost effectiveness of such initiatives is critical in informing policy, it is important to explore whether conventional economic evaluation methods apply to experimental evaluations of policy initiatives. METHODS: We used mixed methods based on a quasi-experimental design to evaluate a policy initiative whose aim was to expedite the modernisation of gastroenterology endoscopy services in England. We compared 10 sites which had received funding and support to modernise their endoscopy services with 10 controls. We collected data from five waves of patients undergoing endoscopy. The economic component of the study compared sites by levels of investment in modernisation and patients' use of health service resources, time off work and health related quality of life. RESULTS: We found no statistically significant difference between intervention and control sites in investment in modernisation or any patient outcome including health. CONCLUSIONS: This study highlights difficulties in applying the rigour of a randomised trial and associated technique of economic evaluation to a policy initiative. It nevertheless demonstrates the feasibility of using this approach although further work is needed to demonstrate its generalisability in other applications. The present application shows that the small incentives offered to intervention sites did not enhance modernisation of gastroenterology endoscopy services or improve patient outcomes.

Single stage treatment of ankylosis of the temporomandibular joint using patient-specific total joint replacement and virtual surgical planning.

Ankylosis of the temporomandibular joint (TMJ) is a debilitating condition that can result in pain, trismus, and a poor quality of life. It can be caused by injury, infection, and rheumatoid disease. Current management includes gap arthroplasty, interpositional arthroplasty, and reconstruction. Traditionally, joints are reconstructed using stock implants, or the procedure is done in two stages with an additional computed tomography (CT) scan between the resective and reconstructive procedures and use of stereolithographic models to aid the design of the definitive prostheses. We describe a technique for the resection of ankylosis and reconstruction of the joint in a single operation using virtually designed custom-made implants. Five patients with ankylosis of the TMJ had a single stage operation with reconstruction between 2010 and 2012. All had preoperative high-resolution CT with contrast angiography. During an international web-based teleconference between the surgeon and the engineer a virtual resection of the ankylosis was done using the reconstructed CT images. The bespoke cutting guides and implants were designed virtually at the same time and were then manufactured precisely using computer-aided design and manufacture (CAD-CAM) over 6 weeks. After release of the ankylosis and reconstruction, the patients underwent an exercise regimen to improve mouth opening. Follow-up was for a minimum of 6 months. Four patients had one operation, and one patient had two. Median/Mean maximum incisal opening increased from 0.6mm before operation to 25 mm afterwards (range 23-27), and there was minimal surgical morbidity. This new method effectively treats ankylosis of the TMJ in a single stage procedure. Fewer operations and hospital stays, and the maintenance of overall clinical outcome are obvious advantages.

A cross-sectional randomised study of fracture risk in people with HIV infection in the probono 1 study.

OBJECTIVE: To determine comparative fracture risk in HIV patients compared with uninfected controls. DESIGN: A randomised cross-sectional study assessing bone mineral density (BMD), fracture history and risk factors in the 2 groups. SETTING: Hospital Outpatients. SUBBBJECTS: 222 HIV infected patients and an equal number of age-matched controls. ASSESSMENTS: Fracture risk factors were assessed and biochemical, endocrine and bone markers measured. BMD was assessed at hip and spine. 10-year fracture probability (FRAX) and remaining lifetime fracture probability (RFLP) were calculated. MAIN OUTCOME MEASURES: BMD, and history of fractures. RESULTS: Reported fractures occurred more frequently in HIV than controls, (45 vs. 16; 20.3 vs. 7%; OR=3.27; p=0.0001), and unsurprisingly in this age range, non-fragility fractures in men substantially contributed to this increase. Osteoporosis was more prevalent in patients with HIV (17.6% vs. 3.6%, p<0.0001). BMD was most reduced, and predicted fracture rates most increased, at the spine. Low BMD was associated with antiretroviral therapy (ART), low body mass index and PTH. 10-year FRAX risk was <5% for all groups. RLFP was greater in patients with HIV (OR=1.22; p=0.003) and increased with ART (2.4 vs. 1.50; OR= 1.50; p=0.03). CONCLUSIONS: The increased fracture rate in HIV patients in our relatively youthful population is partly driven by fractures, including non-fragility fractures, in men. Nonetheless, these findings may herald a rise in osteoporotic fractures in HIV patients. An appropriate screening and management response is required to assess these risks and identify associated lifestyle factors that are also associated with other conditions such as cardiovascular disease and diabetes.

A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: outcomes at 2 years.

OBJECTIVE: The authors performed a randomised trial in very preterm small-for-gestational age (SGA) babies to determine if prophylaxis with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). Despite increased neutrophil counts following GM-CSF, the authors reported no significant difference in neonatal sepsis-free survival. PATIENTS AND METHODS: 280 babies born <31 weeks of gestation and SGA were entered into the trial. Outcome was determined at 2 years to determine neurodevelopmental and general health outcomes, including economic costs. RESULTS: The authors found no significant differences in health outcomes or health and social care costs between the trial groups. In the GM-CSF arm, 87 of 134 (65%) babies survived to 2 years without severe disability compared with 87 of 131 (66%) controls (RR: 1·0, 95% CI 0·8 to 1·2). Marginally, more children receiving GM-CSF were reported to have cough (RR 1·7, 95% CI 1·1 to 2·6) and had signs of chronic respiratory disease (Harrison's sulcus; RR 2·0, 95% CI 1·0 to 3·9) though this was not reflected in bronchodilator use or need for hospitalisation for respiratory disease. Overall, the rate of neurologic abnormality (7%-9%) was similar but mean overall developmental scores were lower than expected for gestational age. CONCLUSIONS: The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse outcomes at 2 years of age. The apparent excess of developmental impairment in the entire PROGRAMS cohort, without corresponding increase in neurological abnormality, may represent diffuse brain injury attributable to intrauterine growth restriction.

Cost effectiveness of alternative planned places of birth in woman at low risk of complications: evidence from the Birthplace in England national prospective cohort study.

OBJECTIVES: To estimate the cost effectiveness of alternative planned places of birth. DESIGN: Economic evaluation with individual level data from the Birthplace national prospective cohort study. SETTING: 142 of 147 trusts providing home birth services, 53 of 56 freestanding midwifery units, 43 of 51 alongside midwifery units, and a random sample of 36 of 180 obstetric units, stratified by unit size and geographical region, in England, over varying periods of time within the study period 1 April 2008 to 30 April 2010. PARTICIPANTS: 64,538 women at low risk of complications before the onset of labour. INTERVENTIONS: Planned birth in four alternative settings: at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units. MAIN OUTCOME MEASURES: Incremental cost per adverse perinatal outcome avoided, adverse maternal morbidity avoided, and additional normal birth. The non-parametric bootstrap method was used to generate net monetary benefits and construct cost effectiveness acceptability curves at alternative thresholds for cost effectiveness. RESULTS: The total unadjusted mean costs were £1066, £1435, £1461, and £1631 for births planned at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units, respectively (equivalent to about €1274, $1701; €1715, $2290; €1747, $2332; and €1950, $2603). Overall, and for multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness when perinatal outcomes were considered. There was, however, an increased incidence of adverse perinatal outcome associated with planned birth at home in nulliparous low risk women, resulting in the probability of it being the most cost effective option at a cost effectiveness threshold of £20 000 declining to 0.63. With regards to maternal outcomes in nulliparous and multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness. CONCLUSIONS: For multiparous women at low risk of complications, planned birth at home was the most cost effective option. For nulliparous low risk women, planned birth at home is still likely to be the most cost effective option but is associated with an increase in adverse perinatal outcomes.

Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy.

OBJECTIVE: To estimate the cost-effectiveness (CE) of total body hypothermia plus intensive care versus intensive care alone to treat neonatal encephalopathy. METHODS: Decision analytic modeling was used to synthesize mortality and morbidity data from three randomized controlled trials, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), National Institute of Child Health and Human Development (NICHD), and CoolCap trials. Cost data inputs were informed by TOBY, the sole source of prospectively collected resource utilization data for encephalopathic infants. CE was expressed in terms of incremental cost per disability-free life year (DFLY) gained. Probabilistic sensitivity analysis was performed to generate CE acceptability curves (CEACs). RESULTS: Cooling led to a cost increase of £3787 (95% confidence interval [CI]: -2516, 12,360) (€5115; 95% CI: -3398-16,694; US$5344; 95% CI: -3598, 26,356; using 2006 Organisation for Economic Co-operation and Development (OECD) purchasing power parities) and a DFLY gain of 0.19 (95%CI: 0.07-0.31) over the first 18 months after birth. The incremental cost per DFLY gained was £19,931 (€26,920; US$28,124). The baseline CEAC showed that if decision-makers are willing to pay £30,000 for an additional DFLY, there is a 69% probability that cooling is cost-effective. The probability of CE exceeded 99% at this threshold when the throughput of infants was increased to reflect the national incidence of neonatal encephalopathy or when the time horizon of the economic evaluation was extended to 18 years after birth. CONCLUSIONS: The probability that cooling is a cost-effective treatment for neonatal encephalopathy is finely balanced over the first 18 months after birth but increases substantially when national incidence data or an extended time horizon are considered.

Cost-effectiveness of heptavalent conjugate pneumococcal vaccine (Prevenar) in Germany: considering a high-risk population and herd immunity effects.

In Germany, the seven-valent conjugate vaccine Prevenar is recommended for use in children at high risk of pneumococcal disease. Recent data suggest that giving conjugate vaccine to all children may lead to a decline in pneumococcal disease in unvaccinated adults, a phenomenon known as herd immunity. This analysis evaluated the cost and economic consequences in Germany of vaccinating (1) children at high risk, (2) all children when considering only benefits for vaccinated individuals and (3) all children when also considering herd immunity benefits. Costs in the model included vaccination, management of meningitis, bacteraemia, pneumonia and acute otitis media, insurance payments to parents and the costs of care for long-term disabilities. The model estimated that the cost-effectiveness of vaccination would be 38,222 euros per life year gained in children at high risk and 100,636 euros per life year gained in all children when not considering herd immunity. When considering herd immunity effects, the model estimated that offering vaccination for all children would reduce adult deaths by 3,027 per year, and vaccination would be broadly cost neutral. The findings are sensitive to the effect of conjugate vaccine on the rates of pneumonia and invasive disease in the elderly. If the herd immunity effect of conjugate vaccination in Germany is similar to that observed elsewhere, offering vaccine to all children will be more attractive than the current policy of restricting vaccination to children at high risk of pneumococcal disease.