Spatio-temporal characterization of fracture healing patterns and assessment of biomaterials by time-lapsed in vivo micro-computed tomography.

Thorough preclinical evaluation of functionalized biomaterials for treatment of large bone defects is essential prior to clinical application. Using in vivo micro-computed tomography (micro-CT) and mouse femoral defect models with different defect sizes, we were able to detect spatio-temporal healing patterns indicative of physiological and impaired healing in three defect sub-volumes and the adjacent cortex. The time-lapsed in vivo micro-CT-based approach was then applied to evaluate the bone regeneration potential of functionalized biomaterials using collagen and bone morphogenetic protein (BMP-2). Both collagen and BMP-2 treatment led to distinct changes in bone turnover in the different healing phases. Despite increased periosteal bone formation, 87.5% of the defects treated with collagen scaffolds resulted in non-unions. Additional BMP-2 application significantly accelerated the healing process and increased the union rate to 100%. This study further shows potential of time-lapsed in vivo micro-CT for capturing spatio-temporal deviations preceding non-union formation and how this can be prevented by application of functionalized biomaterials. This study therefore supports the application of longitudinal in vivo micro-CT for discrimination of normal and disturbed healing patterns and for the spatio-temporal characterization of the bone regeneration capacity of functionalized biomaterials.

Contraceptive prescriptions for US servicewomen, 2008-2013.

OBJECTIVE: To determine the proportion and characteristics of US servicewomen who were prescribed contraception between 2008 and 2013 and to estimate the prevalence of contraceptive utilization among women who deployed during the surveillance period. STUDY DESIGN: This is a descriptive study of all servicewomen of child-bearing potential serving in the active component of the US armed forces at any time between 2008 and 2013. We estimated contraceptive utilization status using pharmacy, procedural and diagnostic codes as recorded in the Defense Medical Surveillance System and Pharmacy Data Transaction Service. Estimates of contraceptive utilization were compared by demographic and military variables, including deployment status. Poisson regression with robust error variance was used to estimate adjusted prevalence ratios and 95% confidence intervals. RESULTS: Among eligible servicewomen (N=375,847), 68.7% received at least one form of contraception during the surveillance period. Contraceptive methods included short acting only (55.6%), long-acting (11.9%), permanent (1.0%) and barrier methods (0.2%). An additional 8.2% received counseling services only without an associated procedure or prescription. After adjusting by several demographic variables, receipt of contraception was highest among women aged 25-29 years and lowest among those aged 17-19 and 45-49 years. Receipt of any contraception was similar across racial/ethnic groups, although Hispanic and black, non-Hispanic women were more likely to receive long-acting reversible contraception. Of those who deployed (N=131,597), 53.6% received contraception before or during their deployment, with 7.9% using long-acting contraception. CONCLUSION: US servicewomen utilize contraception at high levels, with few demographic disparities. Gaps still exist, especially among the youngest women and around the time of deployment. IMPLICATIONS: US servicewomen are prescribed contraception at high levels, but utilization is lower in the youngest servicewomen and around the time of deployment. Such data provide opportunities for development and evaluation of interventions designed to improve access to contraceptive services for all servicewomen and to reduce the rate of unintended pregnancy.

Assessment of rabies exposure risk in a group of U.S. Air Force basic trainees - Texas, January 2014.

In January 2014, members of the Joint Base San Antonio (JBSA)-Lackland, Texas, preventive medicine and public health teams evaluated a U.S. Air Force basic training squadron for potential exposure in sleeping bays to rabies virus carried by Mexican free-tailed bats (Tadarida brasiliensis). Exposure to bats while asleep or otherwise unaware is an important risk factor for rabies in the United States. Over the past several decades, most indigenous human rabies infections in the United States have resulted from the bite of an infected bat, and the bite was not reported in more than half of the cases. Mexican free-tailed bats in Texas often carry rabies virus. Among 8,904 bats tested during 2001-2010, a total of 1,558 (18%) tested positive for rabies. To assess the risk to the Air Force trainees and identify those for whom rabies postexposure prophylaxis (PEP) might be indicated, Lackland preventive medicine and public health teams interviewed 922 persons (866 trainees and 56 instructors) and determined that PEP, consisting of human rabies immune globulin and the 4-dose vaccination series given over 14 days, was indicated for 200 persons (22%). This report describes the public health response to a mass indoor exposure to bats, including group-based rabies risk stratification, adverse reactions to PEP, and infestation remediation. These interventions can be considered for future mass exposures to bats.

Clinical effectiveness and cost-effectiveness of depth of anaesthesia monitoring (E-Entropy, Bispectral Index and Narcotrend): a systematic review and economic evaluation.

BACKGROUND: It is important that the level of general anaesthesia (GA) is appropriate for the individual patient undergoing surgery. If anaesthesia is deeper than required to keep a patient unconscious, there might be increased risk of anaesthetic-related morbidity, such as postoperative nausea, vomiting and cognitive dysfunction. This may also prolong recovery times, potentially increasing health-care costs. If anaesthesia is too light, patients may not be fully unconscious and could be at risk of intraoperative awareness. OBJECTIVE: The objective of this report is to assess the clinical effectiveness and cost-effectiveness of Bispectral Index (BIS), E-Entropy and Narcotrend technologies, each compared with standard clinical monitoring, to monitor the depth of anaesthesia in surgical patients undergoing GA. DATA SOURCES: A search strategy was developed and run on a number of bibliographic electronic databases including MEDLINE, EMBASE, The Cochrane Library and the Health Technology Assessment (HTA) database. For the systematic review of patient outcomes, databases were searched from the beginning of 2009 to November 2011 for studies of BIS (and then updated in February 2012), and from 1995 to November 2011 (and then updated in February 2012) for studies of E-Entropy and Narcotrend. For the systematic review of cost-effectiveness, searches were from database inception to November 2011 (an update search was performed in February 2012). REVIEW METHODS: The systematic review of patient outcomes followed standard methodology for evidence synthesis. A decision-analytic model was developed to assess the cost-effectiveness of depth of anaesthesia monitoring compared with standard clinical observation. A simple decision tree was developed, which accounted for patients' risk of experiencing short-term anaesthetic-related complications in addition to risk of experiencing intraoperative awareness. RESULTS: Twenty-two randomised controlled trials comparing BIS, E-Entropy and Narcotrend with standard clinical monitoring were included in the systematic review of patient outcomes, alongside evidence from a recent Cochrane review. Six trials of patients classified with risk factors for intraoperative awareness were combined in a fixed-effect meta-analysis. The overall pooled Peto's odds ratio was 0.45 (95% confidence interval 0.25 to 0.81) in favour of BIS. However, there was statistically significant heterogeneity. The base-case cost per quality-adjusted life-year (QALY) for BIS compared with standard clinical monitoring ranged from £22,339 to £44,198 depending on patient subgroups (type of GA received; level of risk for awareness). For E-Entropy, base-case estimates ranged from £14,421 to £31,430. For Narcotrend, estimates varied from a cost per QALY of £8033 to Narcotrend dominating standard clinical monitoring. LIMITATIONS: The analysis was limited by lack of clinical effectiveness data, particularly for E-Entropy and Narcotrend. CONCLUSIONS: The available evidence on the impact of the technologies on reducing the likelihood of intraoperative awareness is limited. However, there were reductions in general anaesthetic consumption and anaesthetic recovery times. The cost-effectiveness of depth of anaesthesia monitoring appears to be highly dependent on a number of factors, including probability of awareness. STUDY REGISTRATION: PROSPERO registration number CRD42011001834. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Money as motivation to quit: a survey of a non-random Australian sample of socially disadvantaged smokers' views of the acceptability of cash incentives.

OBJECTIVE: This study aimed to a) assess acceptability of personal financial incentives to socially disadvantaged smokers and non-smokers; b) examine factors associated with acceptability; and c) examine preferred levels of incentive amounts. METHODS: A cross-sectional touch screen computer survey was conducted between February and October 2010 in New South Wales, Australia. Participants were clients experiencing financial or social hardship and receiving emergency welfare aid from a non-government social and community service organisation. RESULTS: Of 383 participants (69% response rate), 46% believed personal financial incentives were an excellent/good idea, 47% believed personal financial incentives did more good than harm and 61% agreed they would motivate smokers to quit. High acceptability ratings were associated with participants being female, current smokers, living in low socioeconomic areas, experiencing smoking-induced deprivation, making a previous quit attempt and intending to quit in the next 6 months. When asked what amount of incentive they felt would be acceptable, 23% selected amounts between $50 and $500 AUD and 37% selected amounts over $500 AUD. CONCLUSIONS: Given high smoking prevalence among socially disadvantaged groups and consequent health disparities, it is imperative novel methods of encouraging smoking cessation are explored and tested. This survey found financial incentives may be an acceptable method. Further research to understand all possible positive and negative effects is warranted.

Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.

BACKGROUND: The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib. OBJECTIVES: This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib. DATA SOURCES: Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references. REVIEW METHODS: This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted. RESULTS: Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are summarised in this report, but caution in interpretation is required. One economic evaluation was identified that compared dasatinib with high-dose imatinib in patients with chronic-phase CML who were CML resistant to standard-dose imatinib. Two industry submissions and the PenTAG economic evaluation were critiqued and differences in the assumptions and results were identified. The PenTAG economic model was adapted and new analyses conducted for the interventions dasatinib, nilotinib and high-dose imatinib and the comparators interferon alfa, standard-dose imatinib, stem cell transplantation and hydroxycarbamide. The results suggest that the three interventions, dasatinib, nilotinib and high-dose imatinib, have similar costs and cost-effectiveness compared with hydroxycarbamide, with a cost-effectiveness of around £30,000 per quality-adjusted life-year gained. However, it is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to great uncertainty around data inputs. Uncertainty was explored using deterministic sensitivity analyses, threshold analyses and probabilistic sensitivity analyses. LIMITATIONS: The paucity of good-quality evidence should be considered when interpreting this report. CONCLUSIONS: This review has identified very limited new information on clinical effectiveness of the interventions over that already shown in the PenTAG report. Limitations in the data exist; however, the results of single-arm studies suggest that the interventions can lead to improvements in haematological and cytogenetic responses in people with imatinib-resistant CML. The economic analyses do not highlight any one of the interventions as being the most cost-effective; however, the analysis results are highly uncertain owing to lack of agreement on appropriate assumptions. Recommendations for future research made by PenTAG, for a good-quality RCT comparing the three treatments remain.

Indicators of sequential fitness assessment failures for Travis Air Force Base airmen who attend the Be Well Course.

PURPOSE: This retrospective community intervention trial evaluated the Be Well course--a mandatory lifestyle intervention course for airmen who fail the U.S. Air Force fitness assessment (FA)--at Travis Air Force Base from November 1, 2010 to February 1, 2011. METHODS: Pre-existing data (N = 276) were analyzed for change in FA scores and for predictors of future outcomes. RESULTS: On the subsequent FA after completing Be Well, males and females scored significantly higher on total points, aerobic fitness, push-ups, and sit-ups (p < 0.001 for all), and males had lower body mass indices (BMI; p = 0.005) and smaller abdominal circumferences (AC; p < 0.001), as compared to their initial FA. As opposed to those who passed the subsequent FA, those who failed consecutively had significantly higher BMIs (p < 0.001), larger ACs (p < 0.001), and lower total scores (p < 0.0001) at the time of the initial failure. CONCLUSIONS: The Be Well course is an effective tool and should remain a component of remedial training for airmen who fail the Air Force FA. Stratification of failure should be considered at the policy level, with special consideration given to the risk factors of high BMI, large AC, and low total FA score.

The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation.

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer in the UK. MM is not curable but can be treated with a combination of supportive measures and chemotherapy that aim to extend the duration and quality of survival. The majority of patients are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation (SCT), and so they are offered single-agent or combination chemotherapy. Combination therapies typically include chemotherapy with an alkylating agent and a corticosteroid. More recently, combination therapies have incorporated drugs such as thalidomide (Thalidomide Celgene®, Celgene) and bortezomib (Velcade®, Janssen-Cilag). OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of bortezomib or thalidomide in combination chemotherapy regimens with an alkylating agent and a corticosteroid for the first-line treatment of MM. DATA SOURCES: Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from 1999 to 2009 for English-language articles. Bibliographies of articles, grey literature sources and manufacturers' submissions were also searched. Experts in the field were asked to identify additional published and unpublished references. REVIEW METHODS: Titles and abstracts were screened for eligibility by two reviewers independently. The inclusion criteria specified in the protocol were applied to the full text of retrieved papers by one reviewer and checked independently by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. A cost-utility decision-analytic model was used to compare the cost-effectiveness estimates of bortezomib in combination with melphalan and prednisolone/prednisone (VMP), thalidomide in combination with cyclophosphamide and attenuated dexamethasone (CTDa), and thalidomide in combination with melphalan and prednisolone/prednisone (MPT) versus melphalan and prednisolone/prednisone (MP). RESULTS: A total of 1436 records were screened and 40 references were retrieved for the systematic review of clinical effectiveness. Five randomised controlled trials (RCTs) met the inclusion criteria for the review: one RCT evaluated VMP, three evaluated MPT and one evaluated CTDa. The comparator in all of the included trials was MP. The review found that VMP and MPT can both be considered more clinically effective than MP for the first-line treatment of MM in people for whom high-dose therapy and SCT would not be appropriate. CTDa was more effective than MP in terms of complete response but data on survival outcomes did not meet the inclusion criteria. Cost-effectiveness analysis indicated that MPT has a greater probability of being cost-effective than either VMP or CTDa. LIMITATIONS: For most RCTs, details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat principles but none adequately reported data censoring. Only one RCT contributed data on VMP and the published peer-reviewed follow-up data were immature. For MPT, overall survival data from two trials were eligible for inclusion but the doses of thalidomide differed between the trials and the treatment period was not reflective of current UK practice so the generalisability of the findings was uncertain. Two RCTs had a maintenance phase with thalidomide that did not meet the inclusion criteria so some of these results were not eligible for the review. Limited evidence on health-related quality of life (HRQoL) was provided by the single trial of VMP versus MP. CONCLUSIONS: Service provision is unlikely to change greatly. As uncertainties remain, further research is needed regarding the use of bortezomib- and thalidomide-containing combination regimens. Head-to-head trials of bortezomib- and thalidomide-containing combination regimes are required, including assessments of patient HRQoL in response to treatment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of long-term weight management schemes for adults: a systematic review.

OBJECTIVE: To assess the long-term clinical effectiveness and cost-effectiveness of multicomponent weight management schemes for adults in terms of weight loss and maintenance of weight loss. DATA SOURCES: Bibliographic databases were searched from inception to December 2009, including the Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences and symposia were searched and experts were contacted to identify additional published and unpublished references. REVIEW METHODS: For the clinical effectiveness review, two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers by one reviewer and checked by a second reviewer using a pre-piloted inclusion flow chart. The studies were long-term randomised controlled trials (RCTs) of adult participants who were classified by body mass index as overweight or obese. Interventions were multicomponent weight management programmes (including diet, physical activity and behaviour change strategies) that assessed weight measures. Programmes that involved the use of over-the-counter medicines licensed in the UK were also eligible. For the cost-effectiveness review two reviewers independently screened studies for inclusion. Cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses were eligible. Data were extracted using a standardised and pre-piloted data extraction form. The quality of included studies was assessed using standard criteria. Studies were synthesised through a narrative review with full tabulation of results. RESULTS: A total of 3358 references were identified, of which 12 were included in the clinical effectiveness review. Five RCTs compared multicomponent interventions with non-active comparator groups. In general, weight loss appeared to be greater in the intervention groups than in the comparator groups. Two RCTs compared multicomponent interventions that focused on the diet component. In these studies there were no statistically significant differences in weight loss between interventions. Four RCTs compared multicomponent interventions that focused on the physical activity component. There was little consistency in the pattern of results seen, in part owing to the differences in the interventions. In one RCT the intervention focused on the goal-setting interval and it appeared that weight loss was greatest in those given daily goals compared with weekly goals. Overall, where measured, it appeared that most groups began to regain weight at further follow-up. Of the 419 studies identified in the cost-effectiveness searches, none met the full inclusion criteria. Two economic evaluations are described in our review; however, caution is required in their interpretation, as they did not meet all inclusion criteria. Lifetime chronic disease models were used in these studies and the models included the costs and benefits of avoiding chronic illness. Both studies found the interventions to be cost-effective, with estimates varying between -£473 and £7200 (US$12,640) per quality-adjusted life-year gained; methodological omissions from these studies were apparent and caution is therefore required in the interpretation of these results. CONCLUSIONS: Long-term multicomponent weight management interventions were generally shown to promote weight loss in overweight or obese adults. Weight changes were small however and weight regain was common. There were few similarities between the included studies; consequently an overall interpretation of the results was difficult to make. There is some evidence that weight management interventions are likely to be cost-effective, although caution is required as there were some limitations in the two cost-evaluation studies described. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia.

Assessment and treatment for hepatitis C virus (HCV) in the community remains low. We evaluated factors associated with HCV specialist assessment and treatment in a cross-sectional study to evaluate treatment considerations in a sample of 634 participants with self-reported HCV infection in New South Wales, Australia. Participants having received HCV specialist assessment (n = 294, 46%) were more likely to be have been older (vs <35 years; 35-44 OR 1.64, P = 0.117; 45-54 OR 2.00, P = 0.024; ≥55 OR 5.43, P = 0.002), have greater social support (vs low; medium OR 3.07, P = 0.004; high OR 4.31, P < 0.001), HCV-related/attributed symptoms (vs none; 1-10 OR 3.89, P = 0.032; 10-21 OR 5.01, P = 0.010), a diagnosis of cirrhosis (OR 2.40, P = 0.030), have asked for treatment information (OR 1.91, P = 0.020), have greater HCV knowledge (OR 2.49, P = 0.001), have been told by a doctor to go onto treatment (OR 3.00, P < 0.001), and less likely to be receiving opiate substitution therapy (OR 0.10, P < 0.001) and never to have seen a general practitioner (OR 0.24, P < 0.001). Participants having received HCV treatment (n = 154, 24%) were more likely to have greater fibrosis (vs no biopsy; none/minimal OR 3.45, P = 0.001; moderate OR 11.47, P < 0.001; severe, OR 19.51, P < 0.001), greater HCV knowledge (OR 2.57; P = 0.004), know someone who has died from HCV (OR 2.57, P = 0.004), been told by a doctor to go onto treatment (OR 3.49, P < 0.001), were less likely to have been female (OR 0.39, P = 0.002), have recently injected (OR 0.42, P = 0.002) and be receiving opiate substitution therapy (OR 0.22, P < 0.001). These data identify modifiable patient-, provider- and systems-level barriers associated with HCV assessment and treatment in the community that could be addressed by targeted interventions.

Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.

BACKGROUND: Recombinant human growth hormone (rhGH) is licensed for short stature associated with growth hormone deficiency (GHD), Turner syndrome (TS), Prader-Willi syndrome (PWS), chronic renal insufficiency (CRI), short stature homeobox-containing gene deficiency (SHOX-D) and being born small for gestational age (SGA). OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of rhGH compared with treatment strategies without rhGH for children with GHD, TS, PWS, CRI, SHOX-D and those born SGA. DATA SOURCES: The systematic review used a priori methods. Key databases were searched (e.g. MEDLINE, EMBASE, NHS Economic Evaluation Database and eight others) for relevant studies from their inception to June 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers, and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. Quality of included studies was assessed using standard criteria, applied by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through a narrative review. RESULTS: Twenty-eight randomised controlled trials (RCTs) in 34 publications were included in the systematic review. GHD: Children in the rhGH group grew 2.7 cm/year faster than untreated children and had a statistically significantly higher height standard deviation score (HtSDS) after 1 year: -2.3 ± 0.45 versus -2.8 ± 0.45. TS: In one study, treated girls grew 9.3 cm more than untreated girls. In a study of younger children, the difference was 7.6 cm after 2 years. HtSDS values were statistically significantly higher in treated girls. PWS: Infants receiving rhGH for 1 year grew significantly taller (6.2 cm more) than those untreated. Two studies reported a statistically significant difference in HtSDS in favour of rhGH. CRI: rhGH-treated children in a 1-year study grew an average of 3.6 cm more than untreated children. HtSDS was statistically significantly higher in treated children in two studies. SGA: Criteria were amended to include children of 3+ years with no catch-up growth, with no reference to mid-parental height. Only one of the RCTs used the licensed dose; the others used higher doses. Adult height (AH) was approximately 4 cm higher in rhGH-treated patients in the one study to report this outcome, and AH-gain SDS was also statistically significantly higher in this group. Mean HtSDS was higher in treated than untreated patients in four other studies (significant in two). SHOX-D: After 2 years' treatment, children were approximately 6 cm taller than the control group and HtSDS was statistically significantly higher in treated children. The incremental cost per quality adjusted life-year (QALY) estimates of rhGH compared with no treatment were: 23,196 pounds for GHD, 39,460 pounds for TS, 135,311 pounds for PWS, 39,273 pounds for CRI, 33,079 pounds for SGA and 40,531 pounds for SHOX-D. The probability of treatment of each of the conditions being cost-effective at 30,000 pounds was: 95% for GHD, 19% for TS, 1% for PWS, 16% for CRI, 38% for SGA and 15% for SHOX-D. LIMITATIONS: Generally poorly reported studies, some of short duration. CONCLUSIONS: Statistically significantly larger HtSDS values were reported for rhGH-treated children with GHD, TS, PWS, CRI, SGA and SHOX-D. rhGH-treated children with PWS also showed statistically significant improvements in body composition measures. Only treatment of GHD would be considered cost-effective at a willingness-to-pay threshold of 20,000 to 30,000 pounds per QALY gained. This analysis suggests future research should include studies of longer than 2 years reporting near-final height or final adult height.

The safety and effectiveness of different methods of earwax removal: a systematic review and economic evaluation.

BACKGROUND: Build-up of earwax is a common reason for attendance in primary care. Current practice for earwax removal generally involves the use of a softening agent, followed by irrigation of the ear if required. However, the safety and benefits of the different methods of removal are not known for certain. OBJECTIVES: To conduct evidence synthesis of the clinical effectiveness and cost-effectiveness of the interventions currently available for softening and/or removing earwax and any adverse events (AEs) associated with the interventions. DATA SOURCES: Eleven electronic resources were searched from inception to November 2008, including: The Cochrane Library; MEDLINE (OVID), PREMEDLINE In-Process & Other Non-Indexed Citations (OVID), EMBASE (OVID); and CINAHL. METHODS: Two reviewers screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text or retrieved papers and data were extracted by two reviewers using data extraction forms developed a priori. Any differences were resolved by discussion or by a third reviewer. Study criteria included: interventions - all methods of earwax removal available and combinations of these methods; participants - adults/children presenting requiring earwax removal; outcomes - measures of hearing, adequacy of clearance of wax, quality of life, time to recurrence or further treatment, AEs and measures of cost-effectiveness; design - randomised controlled trials (RCTs) and controlled clinical trials (CCTs) for clinical effectiveness, cohort studies for AEs and cost-effectiveness, and costing studies for cost-effectiveness. For the economic evaluation, a deterministic decision tree model was developed to evaluate three options: (1) the use of softeners followed by irrigation in primary care; (2) softeners followed by self-irrigation; and (3) a 'no treatment' option. Outcomes were assessed in terms of benefits to patients and costs incurred, with costs presented by exploratory cost-utility analysis. RESULTS: Twenty-six clinical trials conducted in primary care (14 studies), secondary care (8 studies) or other care settings (4 studies), met the inclusion criteria for the review - 22 RCTs and 4 CCTs. The range of interventions included 16 different softeners, with or without irrigation, and in various different comparisons. Participants, outcomes, timing of intervention, follow-up and methodological quality varied between studies. On measures of wax clearance Cerumol, sodium bicarbonate, olive oil and water are all more effective than no treatment; triethanolamine polypeptide (TP) is better than olive oil; wet irrigation is better than dry irrigation; sodium bicarbonate drops followed by irrigation by nurse is more effective than sodium bicarbonate drops followed by self-irrigation; softening with TP and self-irrigation is more effective than self-irrigation only; and endoscopic de-waxing is better than microscopic de-waxing. AEs appeared to be minor and of limited extent. Resuts of the exploratory economic model found that softeners followed by self-irrigation were more likely to be cost-effective [24,433 pounds per quality-adjusted life-year (QALY)] than softeners followed by irrigation at primary care (32,130 pounds per QALY) when compared with no treatment. Comparison of the two active treatments showed that the additional gain associated with softeners followed by irrigation at primary care over softeners followed by self-irrigation was at a cost of 340,000 pounds per QALY. When compared over a lifetime horizon to the 'no treatment' option, the ICERs for softeners followed by self-irrigation and of softeners followed by irrigation at primary care were 24,450 pounds per QALY and 32,136 pounds per QALY, respectively. LIMITATIONS: The systematic review found limited good-quality evidence of the safety, benefits and costs of the different strategies, making it difficult to differentiate between the various methods for removing earwax and rendering the economic evaluation as speculative. CONCLUSIONS: Although softeners are effective, which specific softeners are most effective remains uncertain. Evidence on the effectiveness of methods of irrigation or mechanical removal was equivocal. Further research is required to improve the evidence base, such as a RCT incorporating an economic evaluation to assess the different ways of providing the service, the effectiveness of the different methods of removal and the acceptability of the different approaches to patients and practitioners.

A tutorial on activity-based costing of electronic health records.

As the American Recovery and Restoration Act of 2009 allocates $19 billion to health information technology, it will be useful for health care managers to project the true cost of implementing an electronic health record (EHR). This study presents a step-by-step guide for using activity-based costing (ABC) to estimate the cost of an EHR. ABC is a cost accounting method with a "top-down" approach for estimating the cost of a project or service within an organization. The total cost to implement an EHR includes obvious costs, such as licensing fees, and hidden costs, such as impact on productivity. Unlike other methods, ABC includes all of the organization's expenditures and is less likely to miss hidden costs. Although ABC is used considerably in manufacturing and other industries, it is a relatively new phenomenon in health care. ABC is a comprehensive approach that the health care field can use to analyze the cost-effectiveness of implementing EHRs. In this article, ABC is applied to a health clinic that recently implemented an EHR, and the clinic is found to be more productive after EHR implementation. This methodology can help health care administrators assess the impact of a stimulus investment on organizational performance.

Bortezomib for the treatment of multiple myeloma patients.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of bortezomib for the treatment of multiple myeloma patients at first relapse and beyond, in accordance with the licensed indication, based upon the evidence submission from Ortho Biotech to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were time to disease progression, response rate, survival and quality of life. The literature searches for clinical and cost-effectiveness studies were adequate and the one randomised controlled trial (RCT) included was of reasonable quality. Results from the RCT suggest that bortezomib increases survival and time to disease progression compared with high-dose dexamethasone (HDD) in multiple myeloma patients who have had a relapse after one to three treatments. Cost-effectiveness analysis based on the same trial and an observational study was reasonable and gave an estimated cost per life-year gained of 30,750 pounds, which ranged from 27,957 pounds to 36,747 pounds on sensitivity analysis. An attempt was made to replicate the results of the manufacturer's model and to compare the results to the Kaplan-Meier survival curve presented in the manufacturer's submission. In addition, a one-way sensitivity analysis and a probabilistic sensitivity analysis were undertaken, as well as additional scenario analyses. Based on these analyses the ERG suggests that the cost-effectiveness results presented in the manufacturer's submission may underestimate the cost per life-year gained for bortezomib therapy (versus high-dose dexamethasone) when potential UK practice and scenarios are considered. The guidance issued by NICE in June 2006 as a result of the STA states that bortezomib monotherapy for the treatment of relapsed multiple myeloma is clinically effective compared with HDD but has not been shown to be cost-effective and is not recommended for the treatment of progressive multiple myeloma in patients who have received at least one previous therapy and who have undergone, or are unsuitable for, bone marrow transplantation.

Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

OBJECTIVE: To evaluate DNA testing for detecting hereditary haemochromatosis (HHC) in subgroups of patients suspected of having the disorder and in family members of those diagnosed with HHC. DATA SOURCES: Major electronic databases, searched from inception to April 2007. REVIEW METHODS: A systematic review was undertaken using a priori methods and a de novo model developed to assess costs and consequences of DNA testing. RESULTS: Eleven studies were identified for estimating the clinical validity of genotyping for the C282Y mutation for the diagnosis of HHC. No clinical effectiveness studies meeting the inclusion criteria were identified. Two North American cost-effectiveness studies of reasonable quality were identified but their generalisability to the UK is not clear. Three cohort studies met the inclusion criteria for the review of psychosocial aspects. All had methodological limitations and their generalisability is difficult to determine. The clinical sensitivity of C282Y homozygosity for HHC ranged from 28.4% to 100%, or from 91.3% to 92.4% when considering only the most relevant studies. Clinical specificity ranged from 98.8% to 100%. One study found that gene testing was a cost-effective method of screening relatives of patients with haemochromatosis, whereas the other found that genotyping the spouse of a homozygote was the most cost-efficient strategy. Genetic testing for haemochromatosis appears to be well accepted, is accompanied by few negative psychosocial outcomes and may lead to reduced anxiety. The de novo economic model showed that, in people suspected of having haemochromatosis, the DNA strategy is cost saving compared with the baseline strategy using liver biopsy (cost saved per case detected 123 pounds), largely because of the reduction in liver biopsies. For family testing of siblings the DNA strategy is not cost saving because of the costs of the DNA test (additional cost per case detected 200 pounds). If the cost of the test were to reduce from 100 pounds to 60 pounds, the DNA strategy would be the cheaper one. For family testing of offspring the DNA test strategy is cheaper than the baseline biochemical testing strategy (cost saved per case detected 7982 pounds). Sensitivity analyses showed that the conclusions in each case are robust across all reasonable parameter values. CONCLUSIONS: The preferred strategy in practice is DNA testing in conjunction with testing iron parameters when there is clear clinical indication of risk for haemochromatosis because of biochemical criteria or when there is familial risk for HHC. Access to genetic testing and centralisation of test provision in expert laboratories would lower the cost of testing, improve the cost-effectiveness of the strategy and improve the quality of information provided to clinicians and patients.

Non-occupational postexposure prophylaxis for HIV: a systematic review.

OBJECTIVES: To review the evidence on the clinical effectiveness and cost-effectiveness of non-occupational postexposure prophylaxis (PEP) for HIV. DATA SOURCES: Eleven electronic databases were searched from inception to December 2007. REVIEW METHODS: Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. Studies were synthesised using a narrative approach with full tabulation of results from all included studies. RESULTS: One clinical effectiveness study meeting the inclusion criteria was identified, a cohort study of PEP in a high-risk HIV-negative homosexual male cohort in Brazil. The quality of the study was generally weak. Seroincidence in the cohort as a whole (2.9 per 100 person-years) was very similar to that expected in this population (3.1 per 100 person-years, p > 0.97), despite the seroconversion to HIV being 1/68 in the PEP group and 10/132 in the group not receiving PEP. High-risk sexual activities declined over time for both PEP and non-PEP users. Four economic evaluations met the inclusion criteria of the review. The methodological quality of the studies was mixed. The studies are constrained by a lack of published data on the clinical effectiveness of PEP after non-occupational exposure, with effectiveness data derived from one study of occupational PEP. Their generalisability to the UK is not clear. Results suggest that PEP following non-occupational exposure to HIV was cost saving for men who have unprotected receptive anal intercourse with men, whether the source partner is known to be HIV positive or not; heterosexuals after unprotected receptive anal intercourse; and intravenous drug users sharing needles with a known HIV-positive person. PEP following non-occupational exposure to HIV was cost-effective for all male-male intercourse (unprotected receptive and insertive anal intercourse, unprotected receptive oral sex, and 'other') and was possibly cost-effective for intravenous drug users and high-risk women. Four additional studies were identified giving further information about adverse events associated with PEP after non-occupational exposure to HIV. The majority of participants experienced adverse events with the most common being nausea and fatigue. Rates were generally higher in participants receiving triple therapy than in participants receiving dual therapy. Completion of PEP therapy was variable, ranging from 24% to 78% of participants depending on type of therapy. Toxicity was the main reason for discontinuation of treatment. CONCLUSIONS: It is not possible to draw conclusions on the clinical effectiveness of non-occupational PEP for HIV because of the limited evidence available. The review of cost-effectiveness suggests that non-occupational PEP may be cost-effective, especially in certain population subgroups; however, the assumptions made and data sources used in the cost-effectiveness studies mean that their results should be used with caution.

A decision analysis model for diagnostic strategies using DNA testing for hereditary haemochromatosis in at risk populations.

BACKGROUND: New techniques for diagnosing hereditary haemochromatosis (HHC) have become available alongside traditional tests such as liver biopsy and serum iron studies. AIM: To evaluate DNA tests in people suspected of having haemochromatosis at clinical presentation compared to liver biopsy, and in family members of those diagnosed with haemochromatosis compared to phenotypic iron studies in UK. METHODS: Decision analytic models were constructed to compare the costs and consequences of the diagnostic strategies for a hypothetical cohort of people with suspected haemochromatosis. For each strategy, the number of cases of haemochromatosis identified and treated and the resources used were estimated. RESULTS: For diagnostic strategies in people suspected clinically of having haemochromatosis, the DNA strategy is cost saving compared to liver biopsy (cost saved per case detected, 123 pounds) and continues to be so across all ranges of parameters. For family testing, the DNA strategy is cost saving for the offspring of the proband but not for siblings. If the DNA test cost were to reduce by 40% to 60 pounds or, if in the phenotypic model, those with initially normal iron indices were retested twice instead of once, the DNA strategy would be the cheaper one. CONCLUSION: Diagnostic strategies involving DNA testing are likely to be cost saving in clinical cases with iron overload and in the offspring of index cases. This study supports the UK guideline recommendations for the use of DNA testing in UK.

Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

OBJECTIVES: To review UK guidelines regarding the use of financial incentives for healthcare professionals to become involved in clinical trials, and to survey perceptions and current practice. DATA SOURCES: Electronic databases were searched from inception to June 2006. Interviews were held with NHS healthcare professionals, research managers from the pharmaceutical industry and members of the public. REVIEW METHODS: From the searches, 634 identified studies were assessed for inclusion in the systematic review, but only three met the criteria for data extraction. Fifty-eight individuals were interviewed: 38 chief investigators, six non-research active clinicians, eight public and six pharmaceutical managers. Investigators were selected from those funded by the HTA Programme, the other by 'snowballing' and personal contact. RESULTS: The evidence from the literature was limited and inconclusive. In UK guidelines, the issues around payments to clinicians or patients were implied rather than stated, usually linked to discussion of conflict of interest and disclosure of any such conflicts. Developments in NHS research governance had led to increased transparency in all payments for research participation and for payments to be made to NHS Trusts rather than individual clinicians. While reimbursement of costs incurred by research was strongly supported by the interviewees, payments to incentivise recruitment were not. A code of practice was suggested for payments in publicly funded trials, which was closely linked to the principles of Good Clinical Practice in research. Factors such as interest in the topic, scope for patient benefit and good communication were considered more important than payment. Interviews with the general public indicated low levels of awareness of the existence of payments to clinicians linked to patient recruitment in trials, and unanimous support for full disclosure. Interviews with managers in the pharmaceutical industry showed greater familiarity with payments for research involvement. GPs were seen as the only group for whom scope existed for individual payments. Concerns were expressed by the pharmaceutical company interviewees at the rising cost of research and unnecessary bureaucracy. CONCLUSIONS: The ethical stances outlined in Good Clinical Practice in research were widely endorsed by the three groups interviewed. These allow reasonable payments to clinicians, subject to disclosure of any possible conflicts of interest. The potential for incentivising clinicians to recruit was limited as any payments should be based on the cost of inputs and should not be made to individuals but to their host organisation. NHS professionals were concerned that payments could damage the quality of research and also considered full disclosure to patients as challenging. Patients and members of the public favoured full disclosure and payment of expenses to patients involved in research. Pharmaceutical company interviewees viewed payment to the NHS for all research activities as normal and highly regulated. They complained that the prices charged were high and so variable that they required benchmarking. Considerable scope exists for compiling data on the factors that help and hinder the progress of clinical trials and also for experimenting with different incentives to encourage involvement in clinical research. Further research should focus on improved reporting of those organisational aspects of trials that are known to affect recruitment; retrospective analysis of the factors associated with different levels of recruitment to RCTs; prospective comparative research on trial recruitment; qualitative research on participants' experiences of being involved in different kinds of trials, and proposals to include within trials experiments with payments methods.

A systematic review of the clinical validity and clinical utility of DNA testing for hereditary haemochromatosis type 1 in at-risk populations.

OBJECTIVE: To evaluate the clinical validity and clinical utility of DNA testing in people suspected of having hereditary haemochromatosis and in family members of those diagnosed with the disorder. DESIGN: A systematic review. METHODS: 15 electronic databases were searched up to April 2007. For assessment of the clinical validity of genotyping for the C282Y mutation in the diagnosis of hereditary haemochromatosis, studies were included if they reported the use of DNA tests in Caucasians of northern European origin with iron overload suggestive of haemochromatosis compared with a control population, and reported or allowed calculation of sensitivity and specificity. For clinical utility, studies were included if participants were Caucasians with iron overload suggestive of haemochromatosis or were relatives of suspected cases, if the study compared a diagnostic strategy incorporating DNA testing with one not incorporating DNA testing, and if the study reported patient-based outcomes or some measure of cost effectiveness. RESULTS: 11 studies that could be used to evaluate clinical validity of genotyping for the C282Y mutation in the diagnosis of hereditary haemochromatosis were identified. Clinical sensitivity of C282Y homozygosity for hereditary haemochromatosis ranged from 28.4% to 100%; when considering studies that used strict criteria to classify hereditary haemochromatosis clinical sensitivity ranged from 91.3% to 92.4%. No clinical effectiveness studies were found. Two cost effectiveness studies were identified, both of which suggested that gene testing may be cost effective. CONCLUSION: DNA testing for hereditary haemochromatosis in at-risk populations has clinical validity and may have clinical utility. The review highlights the limitations of the literature and the methodological difficulties associated with evaluating this genetic test.

Environmental sensitivity in New Zealand dairy cattle.

This study quantifies the extent of within-breed sire reranking for milk production traits in a range of environments encountered within New Zealand. Character states of herds were formed within the environmental ranges of herd fat plus protein (MS) yield, summer heat load index (HLI), herd size, and altitude. Single-trait and bivariate sire models across breeds were then applied for estimation of genetic parameters and genetic correlations between extreme character states. A low degree of sire reranking occurred, as measured by genetic correlations around 0.9, between herd environments that differed widely in MS yield (227 vs. 376 kg of MS per cow), and HLI (61.4 vs. 69.6). The HLI of 61.4 and 69.6 are approximately equivalent to average summer maximum temperatures of 19 and 25 degrees C at 80% humidity. Correlations of sire estimated breeding values in extreme character states were low, but only one was below an expected correlation accounting for the reliability of prediction. The results show the environment in New Zealand is not sufficiently diverse to warrant separate breeding schemes for different environments.