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.

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.

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.

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.

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.

The Hippo pathway member YAP enhances human neural crest cell fate and migration.

The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes during development and tumorigenesis. The neural crest is an embryonic tissue known to respond to multiple environmental cues in order to acquire appropriate cell fate and migration properties. Using multiple in vitro models of human neural development (pluripotent stem cell-derived neural stem cells; LUHMES, NTERA2 and SH-SY5Y cell lines), we investigated the role of Hippo/YAP signaling in neural differentiation and neural crest development. We report that the activity of YAP promotes an early neural crest phenotype and migration, and provide the first evidence for an interaction between Hippo/YAP and retinoic acid signaling in this system.

Does Postoperative Radiation Decrease Heterotopic Ossification After the Kocher-Langenbeck Approach for Acetabular Fracture?

BACKGROUND: Controversy regarding heterotopic ossification (HO) prophylaxis exists after Kocher-Langenbeck for treatment of acetabular fracture. Prophylaxis options include antiinflammatory oral medications, single-dose radiation therapy, and débridement of gluteus minimus muscle. Prior literature has suggested single-dose radiation therapy as the best prophylaxis to prevent HO formation. However, recent reports have emerged of radiation-induced sarcoma after radiotherapy for HO prophylaxis, which has led many surgeons to reconsider the risks and benefits of single-dose radiation therapy. We set out to determine if radiotherapy, in addition to standard débridement of gluteus minimus muscle, affected postoperative HO formation after a Kocher-Langenbeck approach for acetabular fracture. QUESTIONS/PURPOSES: (1) After the Kocher-Langenbeck approach and gluteus minimus débridement, is single-dose radiotherapy associated with a decreased risk of HO? (2) Does addition of single-dose radiotherapy prolong length of stay after a Kocher-Langenbeck approach and gluteus minimus débridement as compared with patients without radiotherapy? METHODS: After institutional review board approval, all adult patients treated for acetabular fracture by a single surgeon with a Kocher-Langenbeck approach between August 2011 and October 2014 were identified (n = 60). Débridement of gluteus minimus muscle caudal to the superior gluteal bundle was standard in all patients. Radiotherapy was given with a single dose of 700 cGy within 72 hours of surgery from August 2011 until April 2013. Patients treated subsequently did not receive radiotherapy. Patients treated with indomethacin (n = 1) and with fewer than 10 weeks followup were excluded (n = 12) because several studies suggest that most HO that develops is visible by that point in time. Our study group totaled 46 patients with 24 in the radiotherapy and débridement group and 22 in the débridement group. Charts were reviewed to determine length of stay. Attending orthopaedic trauma surgeons who were blinded to the patient's treatment group graded all followup radiographs according to the Brooker system, and Classes III and IV HO were considered clinically important Fisher's exact test was used to analyze clinically significant differences HO between the two groups. Length of stay was compared using a t-test. RESULTS: Single-dose radiotherapy is associated with a decreased risk of clinically important (Brooker III-IV) HO after a Kocher-Langenbeck approach and gluteus minimus débridement (radiotherapy: one of 24 [4%], no radiotherapy: seven of 22 [32%], relative risk: 0.131 [95% confidence interval {CI}, 0.018-0.981], p = 0.020). Addition of single-dose radiotherapy did not result in increased length of stay (radiotherapy: 12 ± 7.0 days; no radiotherapy: 11 ± 7.2 days; mean difference: 1.0 [95% CI, -3.2 to 5.2] days, p = 0.635). CONCLUSIONS: Single-dose radiation in combination with gluteus minimus débridement decreases the risk of clinically important HO compared with gluteus minimus débridement alone after a Kocher-Langenbeck approach for acetabular fracture. No differences in length of stay were seen. Surgeons who chose not to use radiotherapy as a result of concern for future sarcoma may see higher rates of clinically significant HO after a Kocher-Langenbeck approach for acetabular fracture fixation. LEVEL OF EVIDENCE: Level III, therapeutic study.

Combined flow cytometric analysis of surface and intracellular antigens reveals surface molecule markers of human neuropoiesis.

Surface molecule profiles undergo dynamic changes in physiology and pathology, serve as markers of cellular state and phenotype and can be exploited for cell selection strategies and diagnostics. The isolation of well-defined cell subsets is needed for in vivo and in vitro applications in stem cell biology. In this technical report, we present an approach for defining a subset of interest in a mixed cell population by flow cytometric detection of intracellular antigens. We have developed a fully validated protocol that enables the co-detection of cluster of differentiation (CD) surface antigens on fixed, permeabilized neural cell populations defined by intracellular staining. Determining the degree of co-expression of surface marker candidates with intracellular target population markers (nestin, MAP2, doublecortin, TUJ1) on neuroblastoma cell lines (SH-SY5Y, BE(2)-M17) yielded a combinatorial CD49f(-)/CD200(high) surface marker panel. Its application in fluorescence-activated cell sorting (FACS) generated enriched neuronal cultures from differentiated cell suspensions derived from human induced pluripotent stem cells. Our data underlines the feasibility of using the described co-labeling protocol and co-expression analysis for quantitative assays in mammalian neurobiology and for screening approaches to identify much needed surface markers in stem cell biology.

Surface area and pore size characteristics of nanoporous gold subjected to thermal, mechanical, or surface modification studied using gas adsorption isotherms, cyclic voltammetry, thermogravimetric analysis, and scanning electron microscopy.

Nitrogen adsorption/desorption isotherms are used to investigate the Brunauer, Emmett, and Teller (BET) surface area and Barrett-Joyner-Halenda (BJH) pore size distribution of physically modified, thermally annealed, and octadecanethiol functionalized np-Au monoliths. We present the full adsorption-desorption isotherms for N(2) gas on np-Au, and observe type IV isotherms and type H1 hysteresis loops. The evolution of the np-Au under various thermal annealing treatments was examined using scanning electron microscopy (SEM). The images of both the exterior and interior of the thermally annealed np-Au show that the porosity of all free standing np-Au structures decreases as the heat treatment temperature increases. The modification of the np-Au surface with a self-assembled monolayer (SAM) of C(18)-SH (coverage of 2.94 × 10(14) molecules cm(-2) based from the decomposition of the C(18)-SH using thermogravimetric analysis (TGA)), was found to reduce the strength of the interaction of nitrogen gas with the np-Au surface, as reflected by a decrease in the 'C' parameter of the BET equation. From cyclic voltammetry studies, we found that the surface area of the np-Au monoliths annealed at elevated temperatures followed the same trend with annealing temperature as found in the BET surface area study and SEM morphology characterization. The study highlights the ability to control free-standing nanoporous gold monoliths with high surface area, and well-defined, tunable pore morphology.