Health utility values of breast cancer treatments and the impact of varying quality of life assumptions on cost-effectiveness.

In breast cancer research, utility assumptions are outdated and inconsistent which may affect the results of quality adjusted life year (QALY) calculations and thereby cost-effectiveness analyses (CEAs). Four hundred sixty four female patients with breast cancer treated at Erasmus MC, the Netherlands, completed EQ-5D-5L questionnaires from diagnosis throughout their treatment. Average utilities were calculated stratified by age and treatment. These utilities were applied in CEAs analysing 920 breast cancer screening policies differing in eligible ages and screening interval simulated by the MISCAN-Breast microsimulation model, using a willingness-to-pay threshold of €20,000. The CEAs included varying sets on normative, breast cancer treatment and screening and follow-up utilities. Efficiency frontiers were compared to assess the impact of the utility sets. The calculated average patient utilities were reduced at breast cancer diagnosis and 6 months after surgery and increased toward normative utilities 12 months after surgery. When using normative utility values of 1 in CEAs, QALYs were overestimated compared to using average gender and age-specific values. Only small differences in QALYs gained were seen when varying treatment utilities in CEAs. The CEAs varying screening and follow-up utilities showed only small changes in QALYs gained and the efficiency frontier. Throughout all variations in utility sets, the optimal strategy remained robust; biennial for ages 40-76 years and occasionally biennial 40-74 years. In sum, we recommend to use gender and age stratified normative utilities in CEAs, and patient-based breast cancer utilities stratified by age and treatment or disease stage. Furthermore, despite varying utilities, the optimal screening scenario seems very robust.

Evolution of Value in American College of Cardiology/American Heart Association Clinical Practice Guidelines.

BACKGROUND: In January 2014, the American College of Cardiology/American Heart Association released a policy statement arguing for the inclusion of cost-effectiveness analysis (CEA) and value assessments in clinical practice guidelines. It is unclear whether subsequent guidelines changed how they incorporated such concepts. METHODS: We analyzed guidelines of cardiovascular disease subconditions with a guideline released before and after 2014. We counted the words (total and per page) for 8 selected value- or CEA-related terms and compared counts and rates of terms per page in the guidelines before and after 2014. We counted the number of recommendations with at least 1 reference to a CEA or a CEA-related article to compare the ratios of such recommendations to all recommendations before and after 2014. We looked for the inclusion of the value assessment system recommended by the writing committee of the American College of Cardiology/American Heart Association policy statement of 2014. RESULTS: We analyzed 20 guidelines of 10 different cardiovascular disease subconditions. Seven of the 10 cardiovascular disease subconditions had guidelines with a greater term per page rate after 2014 than before 2014. Across all 20 guidelines, the proportion of recommendations with at least 1 reference to a CEA changed from 0.44% to 1.99% (P<0.01). The proportion of recommendations with at least 1 reference to a CEA-related article changed from 1.02% to 3.34% (P<0.01). Only 3 guidelines used a value assessment system. CONCLUSIONS: The proportion of recommendations with at least 1 reference to a CEA or CEA-related article was low before and after 2014 for most of the subconditions, however, with substantial variation in this finding across the guidelines included in our analysis. There is a need to organize existing CEA information better and produce more policy-relevant CEAs so guideline writers can more easily make recommendations that incentivize high-value care and caution against using low-value care.

Identification of critical ecological areas using the ecosystem multifunctionality-stability-integrity framework: A case study in the Yellow River basin, China.

Critical ecological areas (CEAs), as important regions for biodiversity and ecosystem functions, are crucial for ecological conservation and environmental management at regional and global scales. However, the methodology and framework of CEA identification have not been well established. In this study, a comprehensive CEA identification method was developed based on the ecosystem multifunctionality-stability-integrity framework by using K-means clustering, critical slowing down theory and possible connectivity. Taking the Yellow River basin (YRB) as a case study, our results showed that ecosystem multifunctionality gradually decreased from the southeast to northwest. A decrease in ecosystem stability was observed since 2017 and was mainly due to the increased impacts of human activities and urbanization within the 10-20 km distance threshold from the ecosystem. Based on the proposed framework, 15.13% of the YRB was identified as CEAs with reliable estimates, and most areas were distributed in the Three-River Headwaters, Qinling and Taihang Mountains. Moreover, urbanization and precipitation were found to be the dominant environmental factors affecting the CEA distribution in the YRB. Our results indicated that the proposed framework could provide a comprehensive approach for CEA identification and useful implications for ecological conservation and environmental management.

Guideline Compliant Minimum Asymptomatic Carotid Endarterectomy Surgeon and Hospital Volume Cutoffs.

BACKGROUND: There is a known association between volume and outcomes after carotid endarterectomy (CEA). A recent analysis suggested rates of stroke and death do not significantly reduce after a surgeon volume cutoff of 20 CEAs per year. However, these results would severely limit access. The objective here is to identify a lower optimal cutpoint for surgeon and hospital volume for asymptomatic CEA. METHODS: We evaluated asymptomatic CEA patients using The New York Statewide Planning and Research Cooperative System database from 2000-2014. The relationship of 3-year averaged volumes for surgeons and hospitals to 30-day stroke was assessed using multiple logistic regression and included both hospital and surgeon volume in all analyses. Optimized cut points were the lowest significant volume cutoff that minimized the adjusted odds ratio of stroke. RESULTS: We studied 32,549 CEAs performed by 271 surgeons in 136 centers by vascular surgeons. The median surgeon volume was 26.3 (interquartile range: 12.3-51.7) and the median hospital volume was 67 (interquartile range: 36.3-119.3). The surgeon volume cut point was 3 and the hospital volume cut point was 6 cases per year. There were 756 (2.3%) procedures performed by surgeons with a volume < 3 and 560 (1.7%) procedures performed by hospitals with a volume < 6. Perioperative stroke and death rates were 2.0% (95% confidence interval [CI]: 1.8-2.1) and 3.8% (95% CI: 2.6-5.5) for an average yearly surgeon volume ≥ 3 and < 3 (P = 0.070), respectively. The combined stroke and death rate was 2.0% (95% CI: 1.8-2.1) and 4.8% (95% CI: 3.2-7.0) for an average yearly center volume ≥ 6 and < 6 (P = 0.007), respectively. A combined surgeon and hospital volume variable also predicted outcomes and low-volume procedures did not meet previously proposed American Heart Association and Society for Vascular Surgery quality measures. CONCLUSIONS: These data demonstrate an improvement in outcomes at a lower volume threshold than previously reported. These modest cutoff values should be used for asymptomatic CEA volume guideline formation and for future studies, after accounting for the impact of other important factors that may be driving volume-outcome relationships in asymptomatic CEA.

Capturing the Impact of Constraints on the Cost-Effectiveness of Cell and Gene Therapies: A Systematic Review.

OBJECTIVE: Decision-makers need to resolve constraints on delivering cell and gene therapies to patients as these treatments move into routine care. This study aimed to investigate if, and how, constraints that affect the expected cost and health consequences of cell and gene therapies have been included in published examples of cost-effectiveness analyses (CEAs). METHOD: A systematic review identified CEAs of cell and gene therapies. Studies were identified from previous systematic reviews and by searching Medline and Embase until 21 January 2022. Constraints described qualitatively were categorised by theme and summarised by a narrative synthesis. Constraints evaluated in quantitative scenario analyses were appraised by whether they changed the decision to recommend treatment. RESULTS: Thirty-two CEAs of cell (n = 20) and gene therapies (n = 12) were included. Twenty-one studies described constraints qualitatively (70% cell therapy CEAs; 58% gene therapy CEAs). Qualitative constraints were categorised by four themes: single payment models; long-term affordability; delivery by providers; manufacturing capability. Thirteen studies assessed constraints quantitatively (60% cell therapy CEAs; 8% gene therapy CEAs). Two types of constraint were assessed quantitatively across four jurisdictions (USA, Canada, Singapore, The Netherlands): alternatives to single payment models (n = 9 scenario analyses); improving manufacturing (n = 12 scenario analyses). The impact on decision-making was determined by whether the estimated incremental cost-effectiveness ratios crossed a relevant cost-effectiveness threshold for each jurisdiction (outcome-based payment models: n = 25 threshold comparisons made, 28% decisions changed; improving manufacturing: n = 24 threshold comparisons made, 4% decisions changed). CONCLUSION: The net health impact of constraints is vital evidence to help decision-makers scale up the delivery of cell and gene therapies as patient volume increases and more advanced therapy medicinal products are launched. CEAs will be essential to quantify how constraints affect the cost-effectiveness of care, prioritise constraints to be resolved, and establish the value of strategies to implement cell and gene therapies by accounting for their health opportunity cost.

A Novel Chronic Enteropathy Associated with SLCO2A1 Gene Mutation: Enterography Findings in a Multicenter Korean Registry.

OBJECTIVE: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a recently recognized disease. We aimed to evaluate the enterographic findings of CEAS. MATERIALS AND METHODS: Altogether, 14 patients with CEAS were confirmed based on known SLCO2A1 mutations. They were registered in a multicenter Korean registry between July 2018 and July 2021. Nine of the patients (37.2 ± 13 years; all female) who underwent surgery-naïve-state computed tomography enterography (CTE) or magnetic resonance enterography (MRE) were identified. Two experienced radiologists reviewed 25 and 2 sets of CTE and MRE examinations, respectively, regarding the small bowel findings. RESULTS: In initial evaluation, eight patients showed a total of 37 areas with mural abnormalities in the ileum on CTE, including 1-4 segments in six and > 10 segments in two patients. One patient showed unremarkable CTE. The involved segments were 10-85 mm (median, 20 mm) in length, 3-14 mm (median, 7 mm) in mural thickness, circumferential in 86.5% (32/37), and showed stratified enhancement in the enteric and portal phases in 91.9% (34/37) and 81.8% (9/11), respectively. Perienteric infiltration and prominent vasa recta were noted in 2.7% (1/37) and 13.5% (5/37), respectively. Bowel strictures were identified in six patients (66.7%), with a maximum upstream diameter of 31-48 mm. Two patients underwent surgery for strictures immediately after the initial enterography. Follow-up CTE and MRE in the remaining patients showed minimal-to-mild changes in the extent and thickness of the mural involvement for 17-138 months (median, 47.5 months) after initial enterography. Two patients required surgery for bowel stricture at 19 and 38 months of follow-up, respectively. CONCLUSION: CEAS of the small bowel typically manifested on enterography in varying numbers and lengths of abnormal ileal segments that showed circumferential mural thickening with layered enhancement without perienteric abnormalities. The lesions caused bowel strictures that required surgery in some patients.

Role of mini access during carotid endarterectomy: a prospective observational study.

BACKGROUND: Data from literature confirmed the non-trivial risk associated with carotid revascularization. The purpose of this study is to evaluate carotid endarterectomy (CEA) via a mini-invasive access (3-6 cm longitudinal) incision as a viable alternative to the traditional access via a cutaneous incision (˃6 cm) in terms of nerve sparing and neck pain/disability for patients. METHODS: We performed a prospective, observational, cohort study on 796 consecutive patients who underwent CEAs. A number of 730 patients was included in the final analysis. Patients entered in two different cohorts: CEA with 3-6 cm incision was performed in N.=398 (Group A); CEA with>6 cm incision was performed in N.=398 (Group B). Entire data set is available from 382 in group A and 348 in group B. Adverse events were recorded at 30 days, 3 and 6 months after surgery. The primary purpose of this study was to identify the incidence of cranial nerve injuries and related pain (by Northwick Park Neck Pain Questionnaire [NPq]) in both groups. Differences between groups were exploratory, only, and considered significative for P≤0.05. Secondary objectives were: death, major and minor stroke, transient ischemic attack (TIA), myocardial infarction (MI) and main duration of operation. RESULTS: The cumulative incidence of transient deficit of peripheral nerve in group A was 1.7% at 30 days and 19.4% in group B (RR: 0.10, 95% CI 0.07-0.1, P=0.0001) suggesting a possible benefit from mini-skin incision on nerve injuries reduction. Cranial nerve permanent injuries were identified in 0.17% of mini-incision group and 0.23% of standard group. Exploratory comparison did not demonstrate significative differences between the groups (RR: 0.72, 95% CI 0.19-2.71, P=0.63). The median NPq postoperative score was 40% in GROUP A and 79% in GROUP B (exploratory difference 39%, 95% CI 32.22-45.20%, P=0.0001, χ2: 114.007). At 6 months, NPq was 20% and 42%, respectively; exploratory differences were still present. The need to prolong the mini-incision in GROUP A to preserve the surgical outcome was 1.3%, only. CONCLUSIONS: According to these results the mini skin incision allows a sufficient vessels exposure for dissection, endarterectomy, reconstruction of carotid artery and shunt positioning, minimizing surgical invasiveness, decreasing the incidence of temporary cervical nerve dysfunction and improving the aesthetic result with significative less pain suffered by the patients. Transverse cervical and great auricular nerves sparing decreased postoperative hypo-paresthesia in the neck, improving patient's satisfaction. These data suggest that this procedure can be considered safe. Exploratory analysis suggested that it could possibly be considered a safety alternative to standard carotid endarterectomy. A randomized controlled trial is ongoing for definitive conclusions.

A Novel Chronic Enteropathy Associated with SLCO2A1 Gene Mutation: Enterography Findings in a Multicenter Korean Registry

Objective@#Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a recently recognized disease. We aimed to evaluate the enterographic findings of CEAS. @*Materials and Methods@#Altogether, 14 patients with CEAS were confirmed based on known SLCO2A1 mutations. They were registered in a multicenter Korean registry between July 2018 and July 2021. Nine of the patients (37.2 ± 13 years; all female) who underwent surgery-naïve-state computed tomography enterography (CTE) or magnetic resonance enterography (MRE) were identified. Two experienced radiologists reviewed 25 and 2 sets of CTE and MRE examinations, respectively, regarding the small bowel findings. @*Results@#In initial evaluation, eight patients showed a total of 37 areas with mural abnormalities in the ileum on CTE, including 1–4 segments in six and > 10 segments in two patients. One patient showed unremarkable CTE. The involved segments were 10–85 mm (median, 20 mm) in length, 3–14 mm (median, 7 mm) in mural thickness, circumferential in 86.5% (32/37), and showed stratified enhancement in the enteric and portal phases in 91.9% (34/37) and 81.8% (9/11), respectively. Perienteric infiltration and prominent vasa recta were noted in 2.7% (1/37) and 13.5% (5/37), respectively. Bowel strictures were identified in six patients (66.7%), with a maximum upstream diameter of 31–48 mm. Two patients underwent surgery for strictures immediately after the initial enterography. Follow-up CTE and MRE in the remaining patients showed minimal-to-mild changes in the extent and thickness of the mural involvement for 17–138 months (median, 47.5 months) after initial enterography. Two patients required surgery for bowel stricture at 19 and 38 months of follow-up, respectively. @*Conclusion@#CEAS of the small bowel typically manifested on enterography in varying numbers and lengths of abnormal ileal segments that showed circumferential mural thickening with layered enhancement without perienteric abnormalities. The lesions caused bowel strictures that required surgery in some patients.

A Primer to Cost-Effectiveness Analysis in Breast Cancer Imaging: A Review of the Literature.

Currently, there is a multitude of methods for evaluating the costs and benefits of programs, tools, etc. While cost-benefit analysis (CBA) is commonly used, cost-effectiveness analysis (CEA) is a more appropriate method of evaluation in clinical contexts, such as radiology practices, as CEAs use units such as life years gained as opposed to money (as is the case for CBAs). This review examines CEAs performed within the past 15 years to highlight their applications and key findings in the context of medical imaging. In total, 20 articles published between 2006 and 2022 were identified using a PubMed search for keywords including "cost-effectiveness analysis," "breast cancer," and "medical imaging," with studies lacking a substantial discussion of CEA or a related topic being excluded. CEAs have traditionally been criticized for lack of a standard methodology, despite their utility in the detection and treatment of various pathologies. Although mammography and magnetic resonance imaging (MRI) are the preferred and cost-effective imaging modalities for breast cancer, other imaging modalities, such as contrast-enhanced mammography and digital breast tomosynthesis, may be more cost-effective in the appropriate clinical context. Different combinations of mammography and MRI screenings for certain breast cancers may also prove to be more cost-effective compared to current mammography/MRI screening schedules. While CEA has shown potential utility in estimating the costs (per unit of health gained) of different imaging tools, CEA risks ignoring important outcomes not included in the analysis and cannot address if the benefits of the imaging tool exceed its costs, as a CBA would, suggesting the need for combining several economic evaluations for a more complete understanding.

Cost-effectiveness frameworks for comparing genome and exome sequencing versus conventional diagnostic pathways: A scoping review and recommended methods.

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES. METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening. RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses of costs of ES strategies and postpartum care, as well as genetic diagnoses and pregnancy outcomes. For early diagnosis in pediatrics, modeling quality-adjusted life years (QALYs) and costs over ≥20 years for rapid turnaround GS/ES. For hereditary cancer syndrome testing, modeling cumulative costs and QALYs for the individual tested and first/second/third-degree relatives. For tumor profiling, not restricting to treatment uptake or response and including QALYs and costs of downstream outcomes. For screening, modeling lifetime costs and QALYs and considering consequences of low penetrance and GS/ES reanalysis. CONCLUSION: Our frameworks can guide the design of model-based CEAs and ultimately foster robust evidence for the economic value of GS/ES.

A systematic review of cost-effectiveness analyses on endovascular thrombectomy in ischemic stroke patients.

OBJECTIVE: The objective of this study was to examine the published cost-effectiveness analyses (CEAs) on endovascular thrombectomy (EVT) in acute stroke patients, with a particular focus on the practice of accounting for costs and utilities. METHODS: We conducted a systematic review of published CEAs on EVT in acute stroke patients from 1/1/2009 to 10/1/2019. Published CEAs were searched in Ovid Embase, Ovid MEDLINE, and Web of Science. Cost or comparative effectiveness analyses were excluded. Risk of bias and quality assessment was based on the Consolidated Health Economic Evaluation Reporting Standard checklist. RESULTS: Twenty-one studies were included in the final analysis, from the USA, Canada, Europe, Asia, and Australia. They all concluded EVT to be cost-effective, but with significant variations in methodology. Fifteen studies employed a long-term horizon (> 20 years), while only 11 incorporated risk of recurrent strokes. The willingness-to-pay (WTP) threshold varied from $10,000/quality-adjusted life year (QALY) to $120,000/QALY, with $50,000/QALY and $100,000/QALY being the most commonly used. Five studies undertook a societal perspective, but only one accounted for indirect costs. Seventeen studies based outcomes on 90-day modified Rankin Scale (mRS) scores, and 9 of these 17 studies grouped outcomes by mRS 0-2 and 3-5. Among these 9 studies, the range of QALY score reported for mRS 0-2 was 0.71-0.85 QALY, and that of mRS 3-5 was 0.21-0.40. CONCLUSIONS: Our study reveals significant heterogeneity in previously published thrombectomy CEAs, highlighting need for better standardization in future CEAs. KEY POINTS: • All included studies concluded thrombectomy to be cost-effective, from both long- and short-term perspectives. • Only 5 out of 22 studies undertook a societal perspective, and only 1 accounted for indirect costs. • The range of value for mRS 0-2 was 0.71-0.85 quality-adjusted life year (QALY) and 0.21-0.40 QALY for mRS 3-5.

Herd Immunity Effects in Cost-Effectiveness Analyses among Low- and Middle-Income Countries.

BACKGROUND: Herd immunity (HI) is a key benefit of vaccination programs, but the effects are not routinely included in cost-effectiveness analyses (CEAs). OBJECTIVE: This study investigated how the inclusion of HI in CEAs may influence the reported value of immunizations in low- and middle-income countries (LMICs) and illustrated the implications for COVID-19 immunization. METHODS: We reviewed immunization CEAs published from 2000 to 2018 focusing on LMICs using data from the Tufts Medical Center CEA Registries. We investigated the proportion of studies that included HI, the methods used, and the incremental cost-effectiveness ratios (ICERs) reported. When possible, we evaluated how ICERs would change with and without HI. RESULTS: Among the 243 immunization CEAs meeting inclusion criteria, 44 studies (18%) included HI. Of those studies, 11 (25%) used dynamic transmission models, whereas the remainder used static models. Sixteen studies allowed for ICER calculations with and without HI (n = 48 ratios). The inclusion of HI always resulted in more favorable ratios. In 20 cases (42%), adding HI decreased the ICERs enough to cross at least one or more common cost-effectiveness benchmarks for LMICs. Among pneumococcal vaccination studies, including HI in the analyses decreased seven of 24 ICERs enough to cross at least one cost-effectiveness benchmark. CONCLUSION: The full value of immunization may be underestimated without considering a scenario in which HI is achieved. Given the evidence in pneumococcal CEAs, COVID-19 vaccine value assessments should aim to show ICERs with and without HI to inform decision-making in LMICs.

Completion Arteriogram Following Carotid Endarterectomy Yields Lower Perioperative Stroke Rate.

Introduction: Completion imaging following carotid endarterectomy (CEA) remains controversial. We present our experience performing routine completion arteriography (CA). Methods: A retrospective review of our prospectively maintained institutional database was performed for patients undergoing isolated CEA. Results: 1439 isolated CEAs with CA were performed on 1297 patients. CEA was for asymptomatic lesions in 70% (1003) of cases. There were no complications related to arteriography. An abnormal arteriogram documented significant abnormalities in the internal carotid artery (ICA) and prompted revision in 1.7% (24/1439) of cases: 20 unsatisfactory distal endpoints of the endarterectomy (12 residual stenoses, 7 intimal flaps, and 1 dissection), 3 kinks or stenoses within the body of the patch, and 1 thrombus. Of the 20 distal endpoint lesions, stent deployment was used in 17 cases and patch revision in 3 cases. The other 4 cases were treated by patch angioplasty (3) or thrombectomy (1). None suffered a perioperative stroke. The overall 30-day stroke, death, and combined stroke/death rate for the 1439 patients in our series was 1.5% (22), .5% (7), and 1.9% (27), respectively. The combined stroke/death rate for asymptomatic lesions was 1.1% (11/1003) and for symptomatic lesions was 2.5% (11/436). Of the 22 strokes in the entire series (all with normal CA), 15 were non-hemorrhagic strokes ipsilateral to the CEA; 14 were confirmed to have widely patent endarterectomy sites by CT-A (13) or re-exploration and repeat arteriography (1). The occluded site was re-explored and underwent thrombectomy, but no technical problems were identified. The remaining strokes were hemorrhagic (4 reperfusion syndrome and 1 surgical site bleeding) or contralateral to the CEA (2). Conclusion: Although not all patients in this series who underwent intraoperative revision due to abnormal CA might have suffered a stroke, performing this simple and safe study may have halved our overall perioperative stroke rate from 3.2% to 1.5%.

Microencapsulated Wharton Jelly-derived adult mesenchymal stem cells as a potential new therapeutic tool for patients with COVID-19 disease: an in vitro study.

BACKGROUND: The recent newly appeared Coronavirus disease (COVID-19), caused by an enveloped RNA virus named "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)", is associated with severe respiratory morbidity and mortality. Recent studies have shown that lymphopenia and a cytokine mass release represent important pathogenic features, with clinical evidence of dyspnea and hypoxemia, often leading to acute respiratory distress syndrome (ARDS), in severely ill patients, with a high death toll. Currently, stem cells are actively being investigated for their potential use in many "untreatable" diseases. In this regard and in particular, Mesenchymal Stem Cells (MSC), due to their intrinsic features, including either ability to impact on regulation of the immune system, or association with both anti-viral and anti-inflammatory properties, or potential for differentiation into several cell lineages, have become a promising tool for cell and molecular-based therapies. On this background, we wished to explore whether human umbilical cord-derived mesenchymal stem cells (hUCMS) would represent a potential viable therapeutic approach for the management of critically ill COVID19 patients. METHODS: We tested the hUCMS effects on peripheral blood mononuclear cell (PBMCs) retrieved from patients with COVID19 (Ethical Committee CEAS Umbria, Italy CER N°3658/20 7, May, 2020), both as free cell monolayers and after envelopment in sodium alginate microcapsules. Both cell systems, after priming with IFN-γ, proved able to produce several immunomodulatory molecules such as IDO1 and HLAG5, although only the microencapsulated hUCMS were associated with massive and dose-dependent production of these factors. RESULTS: The microencapsulated hUCMS improved allo-suppression in mixed lymphocytes reactions (MLRs), while also blunting T helper 1 and T helper 17 responses, that are involved with the cytokine storm and greatly contribute to the patient death. Moreover, we observed that both free and microencapsulated hUCMS permitted 5 days survival of in vitro culture maintained PBMCs extracted from very ill patients. CONCLUSION: We have provided evidence that microencapsulated hUCMS in vitro, seem to represent a powerful tool to impact on several immune pathways, clearly deranged in COVID19 patients. Further study is necessary to begin in vivo assessment of this experimental system, upon determining both, the most appropriate time of the disease onset for intervention, and cell dosage/patient of our experimental product.

A Case of Giant Congenital Melanocytic Nevus Treated with Combination Therapy of Autologous Mesh-skin Grafts and Cultured Epithelial Autografts.

Surgical excision of a giant congenital melanocytic nevus (GCMN) results in a full-thickness skin defect that is usually difficult to reconstruct even with tissue expansion or skin grafting. Here, we report the first case of GCMN treated with a combination of cultured epithelial autografts (CEAs) and mesh-skin grafts to reconstruct a large skin defect after surgical excision. A 14-month-old girl had a GCMN occupying 20% of the total body surface area of her neck and back. A 5-stage, full-thickness excision was performed between the age of 14 and 25 months. In each intervention, the wound after excision was covered with 1:6 mesh-skin grafts and CEAs, except for the neck, where patch skin grafts and CEAs were used. The skin grafts and CEAs were engrafted without shedding and epithelialization was completed within 3-4 weeks. Eighteen months after the last surgery, a mesh-like scar remained, with no recurrence or severe contracture observed. The cosmetic appearances of the donor sites (the scalp and lower abdomen) were acceptable. The application of CEAs with mesh-skin grafts has been established for the treatment of severe burns. This combined method also provides a possible option for the treatment of GCMNs.

Analysis of Medicare Payments and Patient Outcomes With Pre-Operative Imaging for Carotid Endarterectomy.

OBJECTIVE: The use of radiographic evaluation of carotid disease may vary, and current guidelines do not strongly recommend the use of cross-sectional imaging (CSI) prior to surgical intervention. We sought to describe the trends in preoperative carotid imaging and evaluate the associated clinical outcomes and Medicare payments for patients undergoing carotid endarterectomy (CEA) for asymptomatic carotid disease. METHODS: We used a 20% Medicare sample from 2006 to 2014 identifying patients undergoing CEA for asymptomatic disease. We evaluated preoperative carotid ultrasound and CSI use: CT or MRI of the neck prior to CEA. We calculated average payments of each study from the carrier file and revenue center file. Imaging payments included both the professional component (PC) and the technical component (TC). Claims with a reimbursement of $0 and studies where payment for both the TC and PC could not be identified were excluded from the overall calculation to determine average payment per study. Inpatient reimbursements according to DRG 37-39 were calculated. We compared hospital length of stay (LOS), in hospital stroke, carotid re-exploration, and mortality according to CSI use. RESULTS: A total of 58,993 CEAs were identified with pre-operative carotid imaging. The average age was 74.8 ± 7.5 years, and 56.0% were men. A total of 19,678 (33%) patients had ultrasound alone with an average of (2.4 ± 1.9) exams prior to CEA. A total of 39,315 patients underwent CSI prior to CEA with 2.5 ± 2.1 ultrasounds, 0.95 ± 0.86 neck CTs and 0.47 ± 0.7 MRIs per patient. The average payment for ultrasound was $140 ± 40, $282 ± 94 for CT and $410 ± 146 for MRI. The average inpatient reimbursements were $7,413 ± 4,215 for patients without CSI compared with $7,792 ± 3,921 for patients with CSI, P < 0.001. The average LOS during CEA admission was 2.5 ± 3.7days. Patients with CSI had a slightly lower percentage of patients being discharged by postoperative day 2 compared with ultrasound alone (88.9% vs. 91.5%, respectively, P < 0.001). The overall in-hospital stroke rate was 0.38% and carotid re-exploration rate was 1.0% and there was no statistical significant difference between groups. Median follow-up was 3.9 years, and mortality at 8 years was 50% and did not statistically differ between groups. CONCLUSIONS: Our analysis found preoperative imaging to include CSI in nearly two-thirds of patients prior to CEA for asymptomatic disease. As imaging and inpatient payments were higher with patients with CSI further work is needed to understand when CSI is appropriate prior to surgical intervention to appropriately allocate healthcare resources.

A multimer-based SERS aptasensor for highly sensitive and homogeneous assay of carcinoembryonic antigens.

Carcinoembryonic antigens (CEAs) are known as one of the most common tumor markers. Their facile and affordable detection is critical for early diagnosis of malignant tumors, especially in resource-constrained settings. Here, we report a novel multimer-based surface-enhanced Raman scattering (SERS) aptasensor for a specific CEA assay. The aptasensor is fabricated through aptamer-assisted self-assembly of silver-coated gold nanoparticles (Au@Ag NPs), and the self-assembled multimeric structure possesses abundant hot-spots to provide high SERS response. When CEA is introduced, the specific recognition of CEA by aptamers will lead to the disassembly of Au@Ag multimers due to the lack of a bridging aptamer between Au@Ag NPs. As a result, the number of hot-spots in the multimeric system is decreased, and the intensity at 1585 cm-1 of the SERS reporter (4-mercaptobenzoic acid, 4-MBA) on the surface of NPs will also be decreased. The Raman intensity is proportional to the logarithm of the concentration of CEA. The detection sensitivity can be down to the pg mL-1 level. The analytical method only needs a droplet of 2 µL of sample, and the detection time is less than 20 min. The multimer-based SERS aptasensor can be applied in sensitive and inexpensive detection of CEA in serum samples.

Cost-Effectiveness of 4CMenB Infant Vaccination in England: A Comprehensive Valuation Considering the Broad Impact of Serogroup B Invasive Meningococcal Disease.

OBJECTIVES: This cost-effectiveness analysis (CEA) of 4CMenB infant vaccination in England comprehensively considers the broad burden of serogroup B invasive meningococcal disease (MenB IMD), which has not been considered, or was only partially considered in previous CEAs. METHODS: A review of previous MenB vaccination CEAs was conducted to identify aspects considered in the evaluation of costs and health outcomes of the disease burden of MenB IMD. To inform the model structure and comprehensive analysis, the aspects were grouped into 5 categories. A stepwise analysis was conducted to analyze the impact of each category, and the more comprehensive consideration of disease burden, on the incremental cost-effectiveness ratio (ICER). RESULTS: MenB IMD incidence decreased by 46.0% in infants and children 0-4 years old within 5 years after introduction of the program. Stepwise inclusion of the 5 disease burden categories to a conventional narrow CEA setting reduced the ICER from £360 595 to £18 645-that is, considering the impact of all 5 categories, 4CMenB infant vaccination is cost-effective at a threshold of £20 000 per QALY gained. CONCLUSIONS: When considering comprehensively the MenB IMD burden, 4CMenB infant vaccination can be cost-effective, a finding contrary to previous CEAs. This analysis allows policy decision-makers globally to infer the impact of current disease burden considerations on the cost-effectiveness and the comprehensive assessment necessary for MenB IMD. Although this comprehensive CEA can help inform decision making today, it may be limited in capturing the full disease burden and complex interactions of health and economics of MenB IMD.

Practice patterns in the use of completion imaging after carotid endarterectomy.

BACKGROUND: The use of intraoperative completion imaging (completion carotid duplex ultrasound or angiography) to confirm the technical adequacy of carotid endarterectomy (CEA) remains a matter of controversy. The purpose of this study was to describe vascular surgeons' practice patterns in the use of completion imaging after CEA and to study the association between completion imaging and postoperative stroke/death and high-grade restenosis (>70%). METHODS: Patients who underwent CEA without concomitant procedures in the Vascular Quality Initiative database between 2003 and 2018 were included. Surgeons' practice patterns were defined on the basis of the distribution of completion imaging use among annual CEA cases per surgeon. Multivariable and Cox proportional hazards models were used to study the association between different practice patterns of completion imaging and perioperative and 1-year outcomes after CEA. RESULTS: Of 98,055 CEA cases, 26,716 (27.3%) were performed with completion imaging. Compared with cases in which completion imaging was not performed, completion imaging was associated with increased rates of immediate re-exploration (3.5% vs 0.9%; odds ratio [OR], 3.84; 95% confidence interval [CI], 2.74-5.38; P < .001), overall return to the operating room (RTOR; 1.6% vs 1.2%; OR, 1.24; 95% CI, 1.08-1.42; P < .01), and longer operative time (median [interquartile range], 105 minutes [82-132] vs 119 minutes [92-148]; P < .001). Of 1920 surgeons in our cohort, 45% never performed completion imaging, whereas 26% rarely performed completion imaging (for ≤20% of annual CEA cases), 9.5% performed it selectively (21%-79% of annual CEAs), and 19.6% used completion imaging routinely (≥80% of annual CEAs). Rarely performing completion imaging had higher rates of immediate re-exploration (6.5% vs 0.9%; OR, 7.2; 95% CI, 5.7-9.2; P < .001), in-hospital stroke (4.0% vs 1.1%; adjusted OR [aOR], 3.4; 95% CI, 2.6-4.6; P < .001), RTOR for bleeding (1.9% vs 0.9%; aOR, 2.1; 95% CI, 1.5-2.9; P < .001), and neurologic events (1.5% vs 0.4%; aOR, 3.6; 95% CI, 2.2-5.9; P < .001) compared with not performing completion imaging. It was also associated with increased stroke/death and repeated revascularization at 30 days and significant restenosis at 1 year. On the other hand, performance of selective and routine completion imaging was associated with increased immediate re-exploration (selective: aOR, 3.2 [95% CI, 1.9-5.5; P < .001]; routine: aOR, 3.7 [95% CI, 2.5-5.6; P < .001]) without any increase in in-hospital, 30-day, and 1-year adverse outcomes compared with cases performed without completion imaging. CONCLUSIONS: The performance of selective or routine completion imaging during CEA is safe and is not associated with increased adverse events compared with not using intraoperative completion imaging. However, rarely performing completion imaging is associated with a significant increase in the odds of perioperative stroke/death and RTOR, possibly because of unnecessary re-exploration for minor defects. The operator's experience and establishing a criterion for fixing residual defects are important to avoid unnecessary re-exploration.

The benefit of deferred carotid revascularization in patients with moderate-severe disabling cerebral ischemic stroke.

OBJECTIVE: Symptomatic carotid artery stenosis needs revascularization within 2 weeks by carotid endarterectomy (CEA) to reduce the risk of symptom recurrence; however, the optimal timing of intervention is yet to be defined in patients with large-volume cerebral ischemic lesion (LVCIL) and modified Rankin scale (mRS) score ≥3. The aim of this study was to determine the most appropriate timing for CEA in patients with a recent stroke and LVCIL. METHODS: Data from patients with symptomatic carotid stenosis with LVCIL and mRS score of 3 or 4 from 2007 to 2017 were considered. Patients were submitted to CEA if they had a stable clinical condition and life expectancy >1 year. LVCIL was defined as a cerebral ischemic lesion of volume >4000 mm3. Perioperative stroke and death were evaluated by stratifying for timing of CEA by χ2 test and multiple logistic regression. Patients with similar characteristics (LVCIL and mRS score of 3 or 4) unfit for CEA served as the control group for recurrence of stroke at 1-year follow-up. RESULTS: In an 11-year period, of a total 4020 CEAs, 126 (2.9%) were performed in patients with a moderate stroke and LVCIL occurring in the same admission. The patients' median age was 69 years (interquartile range [IQR], 10 years); 72% (91) were male, with mRS score of 3 (IQR, 1) and LVCIL volume of 20,000 mm3 (IQR, 47,000 mm3). The median time elapsed from symptoms to CEA was 7 weeks (IQR, 8 weeks). Overall perioperative stroke/death was 7.3% (eight strokes and one death). By selective timing evaluation of the postoperative events, CEA performed within 4 weeks was associated with a significantly higher rate of stroke/death compared with patients operated on after 4 weeks: 11.9% (8/67) vs 1.7% (1/59; P = .03). By logistic regression, CEA within 4 weeks was an independent (from sex, cerebral ischemic lesion volume, dyslipidemia, and carotid stenosis) predictor of postoperative stroke/death (odds ratio, 8.2; 95% confidence interval, 1.01-73). In the same period, 101 patients were considered unfit for CEA for dementia (n = 22), severe comorbidities (n = 55), or short (<1-year) life expectancy (n = 24), and 43 (43%) survived at 1 year. At 1 year, the perioperative/recurrent stroke after CEA vs patients unfit for CEA was similar (6.2% vs 13.9%; P = .11), but CEA performed after 4 weeks led to significantly lower perioperative/recurrent stroke (1.7% vs 13.9%; P = .02). CONCLUSIONS: The surgical risk of CEA in patients with a recent moderate-severe ischemic stroke and LVCIL is high. However, if the intervention is delayed >4 weeks, its benefit seems significant.