The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction: A pooled analysis of DAPA-HF and DELIVER data.

AIM: To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. CONCLUSIONS: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.

Dapagliflozin in chronic kidney disease: cost-effectiveness beyond the DAPA-CKD trial.

Background: The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial enrolled patients with estimated glomerular filtration rate 25-75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio >200 mg/g. The Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial enrolled patients with type 2 diabetes, a higher range of kidney function and no albuminuria criterion. The study objective was to estimate the cost-effectiveness of dapagliflozin in a broad chronic kidney disease population based on these two trials in the UK, Spain, Italy and Japan. Methods: We adapted a published Markov model based on the DAPA-CKD trial but to a broader population, irrespective of urine albumin-to-creatinine ratio, using patient-level data from the DAPA-CKD and DECLARE-TIMI 58 trials. We sourced cost and utility inputs from literature and the DAPA-CKD trial. The analysis considered healthcare system perspectives over a lifetime horizon. Results: Treatment with dapagliflozin was predicted to attenuate disease progression and extend projected life expectancy by 0.64 years (12.5 versus 11.9 years, undiscounted) in the UK, with similar estimates in other settings. Clinical benefits translated to mean quality-adjusted life year (QALY; discounted) gains between 0.45 and 0.68 years across countries. Incremental cost-effectiveness ratios in the UK, Spain, Italy and Japan ($10 676/QALY, $14 479/QALY, $7771/QALY and $13 723/QALY, respectively) were cost-effective at country-specific willingness-to-pay thresholds. Subgroup analyses suggest dapagliflozin is cost-effective irrespective of urinary albumin-to-creatine ratio and type 2 diabetes status. Conclusion: Treatment with dapagliflozin may be cost-effective for patients across a wider spectrum of estimated glomerular filtration rates and albuminuria than previously demonstrated, with or without type 2 diabetes, in the UK, Spanish, Italian and Japanese healthcare systems.

The cost-effectiveness of dapagliflozin in heart failure with preserved or mildly reduced ejection fraction: A European health-economic analysis of the DELIVER trial.

AIMS: To determine the cost-effectiveness of dapagliflozin, added to usual care, in patients with heart failure (HF) with mildly reduced or preserved ejection fraction for the UK, German and Spanish payers using detailed patient-level data from the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial. METHODS AND RESULTS: A lifetime Markov state-transition cohort model was developed. Quartiles of the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) defined health states and monthly transition count data informed transition probabilities. Multivariable generalized estimating equations captured the incidence of HF hospitalizations and urgent HF visits, while cardiovascular deaths and all-cause mortality were estimated using adjusted parametric survival models. Health state costs were assigned to KCCQ-TSS quartiles (2021 British pound [GBP]/Euro) and patient-reported outcomes were sourced from DELIVER. Future values of costs and effects were discounted according to country-specific rates. In the UK, dapagliflozin treatment was predicted to increase quality-adjusted life years (QALYs) and life-years by 0.231 and 0.354, respectively, and extend the time spent in the best quartile of KCCQ-TSS by 4.2 months. Comparable outcomes were projected for Germany and Spain. The incremental cost-effectiveness ratios were £7761, €9540 and €5343/QALY in the UK, Germany and Spain, respectively. According to regional willingness-to-pay thresholds, 91%, 89% and 92% of simulations in the UK, Germany and Spain, respectively, were cost-effective following probabilistic sensitivity analyses. CONCLUSION: Dapagliflozin, added to usual care, is very likely cost-effective for HF with mildly reduced or preserved ejection fraction in several European countries.

Use of the Hybrid Operating Room for Pelvic and Acetabular Fracture Surgery.

The hybrid operating room (HOR) utilizes advanced imaging technology to improve intra-operative visualization and facilitate efficient care in procedures that are relatively image dependent. The robotic C-arm provides improved 2D image quality and is capable of large volume three-dimensional fluoroscopy (3DF) that can rapidly create multiplanar CT like images. Here we discuss on the technique, utility, potential benefits, pitfalls, and complications of using the hybrid suite with and without intra-arterial balloon occlusion for pelvic and acetabular fracture surgery. We also present a case series of patient who underwent pelvic fixation using the HOR. While not advocated for routine use in all pelvic and acetabular fractures; the hybrid suite can be an effective tool in the treatment of complex cases and may facilitate efficient care of the hemodynamically unstable patient. It should be considered when resuscitative stabilization, angioembolization, intra-arterial balloon occlusion, or life-threatening bleeding is anticipated. Additionally, use of the hybrid room allows access to 3D fluoroscopy, and the associated benefits, if a mobile 3D unit is otherwise unavailable. These benefits must be weighed against the cumbersome table, the potential pitfalls with patient size and positioning, and the increased cost to the hospital.

Proportional-assist ventilation with load-adjustable gain factors for mechanical ventilation: a cost-utility analysis.

BACKGROUND: Mechanical ventilation is an important component of patient critical care, but it adds expense to an already high-cost setting. This study evaluates the cost-utility of 2 modes of ventilation: proportional-assist ventilation with load-adjustable gain factors (PAV+ mode) versus pressure-support ventilation (PSV). METHODS: We adapted a published Markov model to the Canadian hospital-payer perspective with a 1-year time horizon. The patient population modelled includes all patients receiving invasive mechanical ventilation who have completed the acute phase of ventilatory support and have entered the recovery phase. Clinical and cost inputs were informed by a structured literature review, with the comparative effectiveness of PAV+ mode estimated via pragmatic meta-analysis. Primary outcomes of interest were costs, quality-adjusted life years (QALYs) and the (incremental) cost per QALY for patients receiving mechanical ventilation. Results were reported in 2017 Canadian dollars. We conducted probabilistic and scenario analyses to assess model uncertainty. RESULTS: Over 1 year, PSV had costs of $50 951 and accrued 0.25 QALYs. Use of PAV+ mode was associated with care costs of $43 309 and 0.29 QALYs. Compared to PSV, PAV+ mode was considered likely to be cost-effective, having lower costs (-$7642) and increased QALYs (+0.04) after 1 year. In cost-effectiveness acceptability analysis, 100% of simulations would be cost-effective at a willingness-to-pay threshold of $50 000 per QALY gained. INTERPRETATION: Use of PAV+ mode is expected to benefit patient care in the intensive care unit (ICU) and be a cost-effective alternative to PSV in the Canadian setting. Canadian hospital payers may therefore consider how best to optimally deliver mechanical ventilation in the ICU as they expand ICU capacity.

Delayed debridement of open tibia fractures beyond 24 and 48 h does not appear to increase infection and reoperation risk.

PURPOSE: Surgical debridement is critical to the treatment of open tibia fractures, although the effects of delayed debridement have not been well-established. Other factors such as Gustilo-Anderson type, prompt initiation of antibiotics, and time to definitive closure may be more predictive of infection than time to surgery. We sought to determine the effect of a prolonged delay to surgical debridement with respect to infection and reoperation rates for open tibia fractures. METHODS: All open diaphyseal tibia fractures with > 12-week follow-up were evaluated. Patient demographics, Gustilo-Anderson type, and rates of deep infection and all-cause reoperation were recorded. Patients were divided into 3 groups based on time to surgery: early (< 24 h), delayed (24-48 h), and late (> 48 h). Univariate and multivariate analyses were performed to evaluate the relationship between time to surgery, fracture type, infection, and reoperation. RESULTS: In total, 96 open tibia fractures with average follow-up of 59.3 weeks and infection rate of 13.5% were included. Infection rates for the early, delayed, and late groups were 13.3%, 17.2%, and 9.1%, respectively (p = 0.70). Reoperation rates for the early, delayed, and late groups were 29.8%, 31.0%, and 22.7%, respectively (p = 0.80). The groups did not vary in proportion of Gustilo-Anderson fracture types; infection rates between Gustilo-Anderson types were similar (p = 0.57). Type IIIA-C fractures required more reoperations than other fracture types (p = 0.01). CONCLUSION: Delayed surgical debridement of open tibia fractures did not result in greater rates of infection or reoperation. Gustilo-Anderson classification was more predictive of reoperation, with Type IIIA-C injuries having a significantly higher reoperation rate.

Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF.

AIMS: Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives. METHODS AND RESULTS: A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. CONCLUSION: Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.

Earlier Provision of Gastric Bypass Surgery in Canada Enhances Surgical Benefit and Leads to Cost and Comorbidity Reduction.

Background: Effective provision of bariatric surgery for patients with obesity may be impeded by concerns of payers regarding costs or perceptions of patients who drop out of surgical programs after referral. Estimates of the cost and comorbidity impact of these inefficiencies in gastric bypass surgery in Canada are lacking but would aid in informing healthcare investment and resource allocation. Objectives: To estimate total and relative public payer costs for surgery and comorbidities (diabetes, hypertension, and dyslipidemia) in a bariatric surgery population. Methods: A decision analytic model for a 100-patient cohort in Canada (91% female, mean body mass index 49.2 kg/m2, 50% diabetes, 66% hypertension, 59% dyslipidemia). Costs include surgery, surgical complications, and comorbidities over the 10-year post-referral period. Results are calculated as medians and 95% credibility intervals (CrIs) for a pathway with surgery at 1 year ("improved") compared with surgery at 3.5 years ("standard"). Sensitivity analyses were performed to test independent contributions to results of shorter wait time, better post-surgical weight loss, and randomly sampled cohort demographics. Results: Compared to standard care, the improved path was associated with reduction in patient-years of treatment for each of the three comorbidities, corresponding to a reduction of $1.1 (0.68-1.6) million, or 34% (26-41%) of total costs. Comorbidity treatment costs were 9.0- and 4.7-fold greater than surgical costs for the standard and improved pathways, respectively. Relative to non-surgical bariatric care, earlier surgery was associated with earlier return on surgical investment and 2-fold reduction in risk of prevalence of each comorbidity compared to delayed surgery. Conclusions: Comorbidity costs represent a greater burden to payers than the costs of gastric bypass surgery. Investments may be worthwhile to reduce wait times and dropout rates and improve post-surgical weight loss outcomes to save overall costs and reduce patient comorbidity prevalence.

Impact of weight trajectory after bariatric surgery on co-morbidity evolution and burden.

BACKGROUND: Bariatric surgery, such as Roux-en-Y gastric bypass [RYGB] has been shown to be an effective intervention for weight management in select patients. After surgery, different patients respond differently even to the same surgery and have differing weight-change trajectories. The present analysis explores how improving a patient's post-surgical weight change could impact co-morbidity prevalence, treatment and associated costs in the Canadian setting. METHODS: Published data were used to derive statistical models to predict weight loss and co-morbidity evolution after RYGB. Burden in the form of patient-years of co-morbidity treatment and associated costs was estimated for a 100-patient cohort on one of 6 weight trajectories, and for real-world simulations of mixed patient cohorts where patients experience multiple weight loss outcomes over a 10-year time horizon after RYGB surgery. Costs (2018 Canadian dollars) were considered from the Canadian public payer perspective for diabetes, hypertension and dyslipidaemia. Robustness of results was assessed using probabilistic sensitivity analyses using the R language. RESULTS: Models fitted to patient data for total weight loss and co-morbidity evolution (resolution and new onset) demonstrated good fitting. Improvement of 100 patients from the worst to the best weight loss trajectory was associated with a 50% reduction in 10-year co-morbidity treatment costs, decreasing to a 27% reduction for an intermediate improvement. Results applied to mixed trajectory cohorts revealed that broad improvements by one trajectory group for all patients were associated with 602, 1710 and 966 patient-years of treatment of type 2 diabetes, hypertension and dyslipidaemia respectively in Ontario, the province of highest RYGB volume, corresponding to a cost difference of $3.9 million. CONCLUSIONS: Post-surgical weight trajectory, even for patients receiving the same surgery, can have a considerable impact on subsequent co-morbidity burden. Given the potential for alleviated burden associated with improving patient trajectory after RYGB, health care systems may wish to consider investments based on local needs and available resources to ensure that more patients achieve a good long-term weight trajectory.

Comparison of Comorbidity Treatment and Costs Associated With Bariatric Surgery Among Adults With Obesity in Canada.

Importance: Information on the associations between barriers to delivery of bariatric surgery and poor weight trajectory afterward is lacking. Estimates are needed to inform decisions by administrators and clinicians to improve care. Objective: To estimate the difference in patient-years of treatment for diabetes, hypertension, and dyslipidemia and public-payer cost between the Canadian standard and an improved bariatric surgery care pathway. Design, Setting, and Participants: Economic evaluation of a decision analytic model comparing the outcomes of the standard care in Canada with an improved bariatric care pathway with earlier sleeve gastrectomy delivery and better postsurgical weight trajectory. The model was informed by published clinical data (101 studies) and meta-analyses (11 studies) between January and May 2019. Participants were a hypothetical 100-patient cohort with demographic characteristics derived from a Canadian study. Interventions: Reduction of Canadian mean bariatric surgery wait time by 2.5 years following referral and improvement of patient postsurgery weight trajectory to levels observed in other countries. Main Outcomes and Measures: Modeling weight trajectory after sleeve gastrectomy and resolution rates for comorbidities in Canada in comparison with an improved care pathway to estimate differences in patient-years of comorbidity treatment over 10 years following referral and the associated costs. Results: For the 100-patient cohort (mean [SD] 88.2% [1.4%] female; mean [SD] age, 43.6 [9.2] years; mean [SD] body mass index, 49.4 [8.2]; and mean [SD] comorbidity prevalence of 50.0% [4.1%], 66.0% [3.9%], and 59.3% [4.0%] for diabetes, hypertension, and dyslipidemia, respectively) over 10 years following referral, the improved vs standard care pathway was associated with median reduction in patient-years of treatment of 324 (95% credibility interval [CrI], 249-396) for diabetes, 245 (95% CrI, 163-356) for hypertension, and 255 (95% CrI, 169-352) for dyslipidemia, corresponding to total savings of $900 000 (95% CrI, $630 000 to $1.2 million) for public payers in the base case. Relative to standard of care, the associated reduction in costs was approximately 29% (95% CrI, 20%-42%) in the improved pathway. Sensitivity analyses demonstrated independent associations of earlier surgical delivery and various levels of postsurgical weight trajectory improvements with overall savings. Conclusions and Relevance: This study suggests that health care burden may be decreased through improvements to delivery and management of patients undergoing sleeve gastrectomy. More data are needed on long-term patient experience with bariatric surgery in Canada to inform better estimates.

Critical Review of European Health-Economic Guidelines for the Health Technology Assessment of Medical Devices.

Background: Health-technology assessment (HTA) is a recognized mechanism to determine the relative benefits of innovative medical technologies. One aspect is their health-economic impact. While the process and methodology for pharmaceuticals is well-established, guidance for medical devices is sparse. Aim: To provide an overview of the health-economic aspect in current European HTA guidelines concerning medical devices and identifying issues raised and potential improvements proposed in recent literature. Methodology: Available guidelines by European agencies were each reviewed and summarized. To complement this, a full systematic review of current literature concerning potential improvements to existing HTA practices for medical devices, from PubMed and EMBASE, was conducted; the focus was on health economics. Authors could only review documents in English, French, or German. The systematic review yielded 518 unique articles concerning HTA for medical devices, 32 of which were considered for full-text review after screening of all abstracts. Results: There is very limited consensus in-and mostly a complete lack of-guidance specific to medical devices in official HTA guidelines, for both clinical and economic analyses. Twenty two of 41 European countries had published official HTA guidance in English, French, or German. Among these only 4 (England, France, the Netherlands, and Sweden) dedicated a chapter or separate document to medical devices. In the literature, there is sufficient evidence to suggest medical devices need to be addressed separately from pharmaceuticals. However, mostly challenges are discussed rather than implementable solutions offered. We present the following set of frequently discussed issues and summarize any solutions that pertain to them: a weak evidence base, learning-curve effects, organizational impact, incremental innovation, diversity of devices, dynamic pricing, and transferability. We further combine reviewed information to suggest a set of possible best practices for health-economic assessment of medical devices. Conclusion: For greater efficiency in medical-device innovation, European agencies should look to (re-)address the specific requirements of medical devices in their HTA guidelines. When both the health-economic and data requirements for the HTA of medical devices are defined, the development of practical solutions will likely follow.

Assessing the Value of Routine Pathologic Examination of Resected Femoral Head Specimens After Femoral Neck Fracture.

INTRODUCTION: The purpose of this study was to evaluate the efficacy of routine pathologic examination (PE) of femoral head (FH) specimens after arthroplasty for acute femoral neck fractures and to determine the cost. METHODS: This was a retrospective chart review of 850 acute femoral neck fractures treated with hemiarthroplasty or total hip arthroplasty These were evaluated to determine whether the FH was sent for PE, the resultant findings, alterations in medical treatment, and cost. RESULTS: A total of 466 FH specimens (54.8%) were sent to pathology. Four (0.9%) were positive for a neoplastic process. All four had a known history of cancer, antecedent hip pain, or an inappropriate injury mechanism. None of the findings resulted in an alteration in medical treatment. The average cost of PE was $195 USD. DISCUSSION: The routine PE of FH specimens after arthroplasty for femoral neck fractures is not warranted and uneconomic. Sending the FH for PE, only when clinically indicated, rather than routine, will result in notable savings for the healthcare system. LEVEL OF EVIDENCE: Level IV.

Brake response time after modern total knee arthroplasty: How soon can patients drive?

BACKGROUND: Recent advances in the performance of total knee arthroplasty may allow for return to driving sooner than the current recommendation of six to eight weeks. The purpose of this study was to evaluate at what time point patients may safely return to driving after modern total knee arthroplasty. METHODS: Thirty-two consecutive patients underwent pre-operative and weekly post-operative assessments of brake reaction time before and for eight weeks after undergoing total knee arthroplasty. RESULTS: Overall, patients returned to their preoperative baseline brake reaction times by the second postoperative week. There was a significant difference in regard to gender but not laterality or age. Specifically, men achieved preoperative brake reaction times by the first postoperative week and women by the second. CONCLUSIONS: Patients undergoing total knee arthroplasty with a modern perioperative pathway appear to achieve preoperative brake reaction times by the second postoperative week when not taking narcotic pain medication. However, the safe return to driving in each patient must be approached individually. Surgeon discretion to release a patient to drive is always prudent and the decision should be considered on an individual basis.

Freiburg RNA tools: a central online resource for RNA-focused research and teaching.

The Freiburg RNA tools webserver is a well established online resource for RNA-focused research. It provides a unified user interface and comprehensive result visualization for efficient command line tools. The webserver includes RNA-RNA interaction prediction (IntaRNA, CopraRNA, metaMIR), sRNA homology search (GLASSgo), sequence-structure alignments (LocARNA, MARNA, CARNA, ExpaRNA), CRISPR repeat classification (CRISPRmap), sequence design (antaRNA, INFO-RNA, SECISDesign), structure aberration evaluation of point mutations (RaSE), and RNA/protein-family models visualization (CMV), and other methods. Open education resources offer interactive visualizations of RNA structure and RNA-RNA interaction prediction as well as basic and advanced sequence alignment algorithms. The services are freely available at http://rna.informatik.uni-freiburg.de.

Clinical and economic burden of procedural sedation-related adverse events and their outcomes: analysis from five countries.

BACKGROUND: Studies have reported on the incidence of sedation-related adverse events (AEs), but little is known about their impact on health care costs and resource use. METHODS: Health care providers and payers in five countries were recruited for an online survey by independent administrators to ensure that investigators and respondents were blinded to each other. Surveys were conducted in the local language and began with a "screener" to ensure that respondents had relevant expertise and experience. Responses were analyzed using Excel and R, with the Dixon's Q statistic used to identify and remove outliers. Global and country-specific average treatment patterns were calculated via bootstrapping; costs were mean values. The sum product of costs and intervention probability gave a cost per AE. RESULTS: Responses were received from 101 providers and 26 payers, the majority having >5 years of experience. At a minimum, the respondents performed a total of 3,430 procedural sedations per month. All AEs detailed occurred in clinical practice in the last year and were reported to cause procedural delays and cancellations in some patients. Standard procedural sedation costs ranged from €74 (Germany) to $2,300 (US). Respondents estimated that AEs would increase costs by between 16% (Italy) and 179% (US). Hypotension was reported as the most commonly observed AE with an associated global mean cost (interquartile range) of $43 ($27-$68). Other frequent AEs, including mild hypotension, bradycardia, tachycardia, mild oxygen desaturation, hypertension, and brief apnea, were estimated to increase health care spending on procedural sedation by $2.2 billion annually in the US. CONCLUSION: All sedation-related AEs can increase health care costs and result in substantial delays or cancellations of subsequent procedures. The prevention of even minor AEs during procedural sedation may be crucial to ensuring its value as a health care service.

Combinatorial ensemble miRNA target prediction of co-regulation networks with non-prediction data.

MicroRNAs (miRNAs) are key regulators of cell-fate decisions in development and disease with a vast array of target interactions that can be investigated using computational approaches. For this study, we developed metaMIR, a combinatorial approach to identify miRNAs that co-regulate identified subsets of genes from a user-supplied list. We based metaMIR predictions on an improved dataset of human miRNA-target interactions, compiled using a machine-learning-based meta-analysis of established algorithms. Simultaneously, the inverse dataset of negative interactions not likely to occur was extracted to increase classifier performance, as measured using an expansive set of experimentally validated interactions from a variety of sources. In a second differential mode, candidate miRNAs are predicted by indicating genes to be targeted and others to be avoided to potentially increase specificity of results. As an example, we investigate the neural crest, a transient structure in vertebrate development where miRNAs play a pivotal role. Patterns of metaMIR-predicted miRNA regulation alone partially recapitulated functional relationships among genes, and separate differential analysis revealed miRNA candidates that would downregulate components implicated in cancer progression while not targeting tumour suppressors. Such an approach could aid in therapeutic application of miRNAs to reduce unintended effects. The utility is available at http://rna.informatik.uni-freiburg.de/metaMIR/.

Treatment of Infected Forearm Nonunions With Large Complete Segmental Defects Using Bulk Allograft and Intramedullary Fixation.

PURPOSE: The purpose of this study is to report the results of a series of infected forearm nonunions treated from 1998 to 2012 using a staged reconstruction technique. METHODS: At a median of 42 months follow-up, 7 patients who had an average segmental defect of 4.9 cm (range, 2.3-10.4 cm) were available for clinical and radiographic evaluation. Treatment consisted of serial debridement, implantation of an antibiotic cement spacer, and staged reconstruction using a bulk radius or ulna allograft with intramedullary fixation. RESULTS: All 7 patients ultimately achieved solid bone union, although 4 patients (57%) required additional surgery, consisting of autologous bone grafting and plating, to achieve healing at 1 of the allograft-host junction sites. No patient had recurrence of infection, and all reported substantial improvement with increased function and decreased pain. CONCLUSIONS: Our approach ultimately resulted in a 100% union rate without recurrence of infection, although many patients may require additional surgery to attain healing at both allograft-junction sites. Using bulk allograft provides the ability to span a large defect while reconstituting the forearm anatomy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.