Immunohistochemical Characterization of Proliferative Lesions in the Thymus of Aging CD-1 Mice From Two Studies on the RITA Database, With Special Reference to the Perivascular Space.

Thymic lymphoid hyperplasia is a common age-related finding, which occurs particularly in female CD-1 mice. The main differential diagnoses are malignant lymphoma and thymoma. A systematic investigation of control groups from two carcinogenicity studies was performed including measurements of thymic size, and the immunohistochemistry (IHC) markers pan-Cytokeratin (pan-CK) for thymic epithelial cells; CD3 and CD45R/B220 for T and B lymphocytes, respectively; CD31 for endothelial cells; and F4/80 for macrophages. Thymoma can be differentiated by increased numbers of proliferating epithelial cells demonstrated by pan-CK IHC staining. Differentiation between lymphoid hyperplasia and lymphoma is more challenging as a mixture of B and T lymphocytes can be present in both findings. The present investigation showed that the thymic perivascular space is the compartment where the increased numbers of lymphocytes in hyperplasia are localized and not the medulla, as previously thought. The lymphoepithelial compartment is atrophic to the same extent in thymi diagnosed with age-related involution or lymphoid hyperplasia. Both diagnoses are thus related to variations in lymphoid cellularity of the nonepithelial perivascular space, which is continuous with the perithymic tissue. Likewise, lymphomas have a predilection to colonize the perivascular space and to spare the lymphoepithelial compartment.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Economic analysis of the adoption of capsule endoscopy within the British NHS.

OBJECTIVE: Identification of a cost-effective treatment strategy is an unmet need in Crohn's disease (CD). Here we consider the patient outcomes and cost impact of pan-intestinal video capsule endoscopy (PVCE) in the English National Health Service (NHS). DESIGN: An analysis of a protocolized CD care pathway, informed by guidelines and expert consensus, was performed in Microsoft Excel. Population, efficacy and safety data of treatments and monitoring modalities were identified using a structured PubMed review with English data prioritized. Costs were taken from the NHS and Payer Provided Services (PSS) 2016-17 tariffs for England and otherwise literature. Analysis was via a discrete-individual simulation with discounting at 3.5% per annum. SETTING: NHS provider and PSS perspective. PARTICIPANTS: 4000 simulated CD patients. INTERVENTIONS: PVCE versus colonoscopy ± magnetic resonance enterography (MRE). MAIN OUTCOME MEASURES: Costs in 2017 GBP and quality-adjusted life years (QALY). RESULTS: The mean, total 20-year cost per patient was £42 266 with colonoscopy ± MRE and £38 043 with PVCE. PVCE incurred higher costs during the first 2 years due to higher treatment uptake. From year 3 onwards, costs were reduced due to fewer surgeries. Patients accrued 10.67 QALY with colonoscopy ± MRE and 10.96 with PVCE. PVCE dominated (less cost and higher QALY) colonoscopy ± MRE and was likely (>74%) to be considered cost-effective by the NHS. Results were similar if a lifetime time horizon was used. CONCLUSIONS: PVCE is likely to be a cost-effective alternative to colonoscopy ± MRE for CD surveillance. Switching to PVCE resulted in lower treatment costs and gave patients better quality of life.

Tuning of Differential Lipid Order Between Submicrometric Domains and Surrounding Membrane Upon Erythrocyte Reshaping.

BACKGROUND/AIMS: Transient nanometric cholesterol- and sphingolipid-enriched domains, called rafts, are characterized by higher lipid order as compared to surrounding lipids. Here, we asked whether the seminal concept of highly ordered rafts could be refined with the presence of lipid domains exhibiting different enrichment in cholesterol and sphingomyelin and association with erythrocyte curvature areas. We also investigated how differences in lipid order between domains and surrounding membrane (bulk) are regulated and whether changes in order differences could participate to erythrocyte deformation and vesiculation. METHODS: We used the fluorescent hydration- and membrane packing-sensitive probe Laurdan to determine by imaging mode the Generalized Polarization (GP) values of lipid domains vs the surrounding membrane. RESULTS: Laurdan revealed the majority of sphingomyelin-enriched domains associated to low erythrocyte curvature areas and part of the cholesterol-enriched domains associated with high curvature. Both lipid domains were less ordered than the surrounding lipids in erythrocytes at resting state. Upon erythrocyte deformation (elliptocytes and stimulation of calcium exchanges) or membrane vesiculation (storage at 4°C), lipid domains became more ordered than the bulk. Upon aging and in membrane fragility diseases (spherocytosis), an increase in the difference of lipid order between domains and the surrounding lipids contributed to the initiation of domain vesiculation. CONCLUSION: The critical role of domain-bulk differential lipid order modulation for erythrocyte reshaping is discussed in relation with the pressure exerted by the cytoskeleton on the membrane.

Enumeration and Localization of Mesenchymal Progenitor Cells and Macrophages in Synovium from Normal Individuals and Patients with Pre-Osteoarthritis or Clinically Diagnosed Osteoarthritis.

Osteoarthritis (OA) is a degenerative disorder characterized by chondrocyte apoptosis and degeneration of articular cartilage resulting in loss of mobility and pain. Inflammation plays a key role in the development and progression of OA both on the side of apoptosis and repair, while its exact role in pathogenesis has yet to be fully elucidated. Few studies have examined the cellular composition (inflammatory cells and/or progenitor cells) in the synovium of patients with pre-OA (asymptomatic with cartilage damage). Therefore, in the current study, mesenchymal progenitor cells (MPCs) and macrophages were enumerated within normal, pre-OA and OA synovium. No differences were observed between MPCs in normal vs. pre-OA, however, fewer macrophages were observed in pre-OA vs. normal synovium. Osteoarthritic synovium contained greater numbers of both MPCs and macrophages. Interestingly, the localization of MPCs and macrophages was affected by disease severity. In normal and pre-OA synovium, MPCs and macrophages co-localized, while in OA synovium, MPCs and macrophage populations were spatially distinct. Examining the cellular interactions between MPCs and macrophages in synovium may be essential for understanding the role of these cells in the onset and/or pathogenesis of the disease. This study has provided a first step by examining these cell types both spatially and temporally (e.g., disease severity). Further cellular and molecular studies will be needed to determine the functions of these cells in the context of disease and in relation to each other and the joint as a whole.

α-Hederin Induces Apoptosis, Membrane Permeabilization and Morphologic Changes in Two Cancer Cell Lines Through a Cholesterol-Dependent Mechanism.

In perspective of reducing the mortality of cancer, there is a high interest in compounds which act on multiple cellular targets and therefore prevent the appearance of cancer resistances. Saponins and α-hederin, an oleanane-type saponin, induce cancer cell death through different pathways, including apoptosis and membrane permeabilization. Unfortunately, the mechanism by which cell death is induced is unknown. We hypothesized that the activity of α-hederin mainly depends on its interaction with membrane cholesterol and therefore investigated the cholesterol and saponin-structure dependency of apoptosis and membrane permeabilization in two malignant monocytic cell lines. Apoptotic cell death and membrane permeabilization were significantly reduced in cholesterol-depleted cells. Permeabilization further depended upon the osidic side chain of α-hederin and led to extracellular calcium influx and nuclear fragmentation, with only the latter being susceptible to caspase inhibitors. Membrane order, measured by laurdan generalized polarization imaging, was neither reduced by α-hederin nor its aglycone hederagenin suggesting that their activity was not related to membrane cholesterol extraction. However, a radical change in morphology, including the disappearance of pseudopodes was observed upon incubation with α-hederin. Our results suggest that the different activities of α-hederin mainly depend on its interaction with membrane cholesterol and consequent pore formation.

A Cost-Effectiveness Analysis of Minimally Invasive versus Open Surgery Techniques for Lumbar Spinal Fusion in Italy and the United Kingdom.

OBJECTIVE: Evaluate the cost-effectiveness of minimally invasive surgery (MIS) compared with open surgery (OS) techniques for one- or two-level lumbar spinal fusion in the treatment of degenerative lumbar spinal conditions in the United Kingdom and Italy. METHODS: A health economic model was developed on the basis of results from a systematic literature review and meta-analysis to determine the cost-effectiveness of MIS compared with OS for lumbar spinal fusion. The analysis was conducted from a health care payer perspective. Parameters included in the model were surgery, blood loss, duration of hospitalization, postoperative complications, and health-related quality of life (HRQOL). Cost-effectiveness was determined by the incremental cost per quality-adjusted life-year gained. RESULTS: MIS was the dominant strategy compared with OS (i.e., yielding both cost savings and improved HRQOL). Cost savings were driven mainly by shorter length of hospital stay, reduced blood loss, and fewer complications such as surgical site infection. The total cost saving per procedure was €973 for Italy and €1666 for the United Kingdom, with an improvement of 0.04 quality-adjusted life-year over 2 years in HRQOL. One-way sensitivity analyses and predefined scenario(s) analyses confirmed the robustness of the model. CONCLUSIONS: MIS is a less expensive and a more effective treatment compared with OS for spinal lumbar fusion in both Italy and the United Kingdom. Lower downstream costs and increased HRQOL in the MIS group compensate for potential higher upfront costs of MIS implants and surgery equipment.

Screening for psychotic experiences and psychotic disorders in general psychiatric settings: a systematic review and meta-analysis.

Background: The absence of systematic screening for psychosis within general psychiatric services contribute to substantial treatment delays and poor long-term outcomes. We conducted a meta-analysis to estimate rates of psychotic experiences, clinical high-risk for psychosis syndrome (CHR-P), and psychotic disorders identified by screening treatment-seeking individuals to inform implementation recommendations for routine psychosis screening in general psychiatric settings. Methods: PubMed and Web of Science databases were searched to identify empirical studies that contained information on the point prevalence of psychotic experiences, CHR-P, or psychotic disorders identified by screening inpatient and outpatient samples aged 12-64 receiving general psychiatric care. Psychotic experiences were identified by meeting threshold scores on validated self-reported questionnaires, and psychotic disorders and CHR-P by gold-standard structured interview assessments. A meta-analysis of each outcome was conducted using the Restricted Maximum Likelihood Estimator method of estimating effect sizes in a random effects model. Results: 41 independent samples (k=36 outpatient) involving n=25,751 patients (58% female, mean age: 24.1 years) were included. Among a general psychiatric population, prevalence of psychotic experiences was 44.3% (95% CI: 35.8-52.8%; 28 samples, n=21,957); CHR-P was 26.4% (95% CI: 20.0-32.7%; 28 samples, n=14,395); and psychotic disorders was 6.6% (95% CI: 3.3-9.8%; 32 samples, n=20,371). Conclusions: High rates of psychotic spectrum illness in general psychiatric settings underscore need for secondary prevention with psychosis screening. These base rates can be used to plan training and resources required to conduct assessments for early detection, as well as build capacity in interventions for CHR-P and early psychosis in non-specialty mental health settings.

Production of Mesenchymal Progenitor Cell-Derived Extracellular Vesicles in Suspension Bioreactors for Use in Articular Cartilage Repair.

Mesenchymal progenitor cells (MPCs) have shown promise initiating articular cartilage repair, with benefits largely attributed to the trophic factors they secrete. These factors can be found in the conditioned medium (CM) collected from cell cultures, and it is believed that extracellular vesicles (EVs) within this CM are at least partially responsible for MPC therapeutic efficacy. This study aimed to examine the functionality of the EV fraction of CM compared to whole CM obtained from human adipose-derived MPCs in an in vivo murine cartilage defect model. Mice treated with whole CM or the EV fraction demonstrated an enhanced cartilage repair score and type II collagen deposition at the injury site compared to saline controls. We then developed a scalable bioprocess using stirred suspension bioreactors (SSBs) to generate clinically relevant quantities of MPC-EVs. Whereas static monolayer culture systems are simple to use and readily accessible, SSBs offer increased scalability and a more homogenous environment due to constant mixing. This study evaluated the biochemical and functional properties of MPCs and their EV fractions generated in static culture versus SSBs. Functionality was assessed using in vitro MPC chondrogenesis as an outcome measure. SSBs supported increased MPC expression of cartilage-specific genes, and EV fractions derived from both static and SSB culture systems upregulated type II collagen production by MPCs. These results suggest that SSBs are an effective platform for the generation of MPC-derived EVs with the potential to induce cartilage repair.

Synovial fluid mesenchymal progenitor cells from patients with juvenile idiopathic arthritis demonstrate limited self-renewal and chondrogenesis.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases affecting joints with a prevalence of one in a thousand children. There is a growing body of literature examining the use of mesenchymal stem/progenitor cells (MPCs) for the treatment of adult and childhood arthritis, however, we still lack a clear understanding of how these MPC populations are impacted by arthritic disease states and how this could influence treatment efficacy. In the current study we examined the immunophenotyping, self-renewal ability and chondrogenic capacity (in vitro and in vivo) of synovial derived MPCs from normal, JIA and RA joints. Synovial MPCs from JIA patients demonstrated reduced self-renewal ability and chondrogenic differentiation capacity. Furthermore, they did not induce cartilage regeneration when xenotransplanted in a mouse cartilage injury model. Synovial MPCs from JIA patients are functionally compromised compared to MPCs from normal and/or RA joints. The molecular mechanisms behind this loss of function remain elusive. Further study is required to see if these cells can be re-functionalized and used in cell therapy strategies for these JIA patients, or if allogenic approaches should be considered.

Service Evaluation of the Impact of Capnography on the Safety of Procedural Sedation.

Background: Capnography has been associated with a reduced incidence of events related to respiratory compromise during procedural sedation. Methods: A prospective service evaluation was conducted at a large United Kingdom (UK) teaching hospital to assess the impact of capnography on patient safety within four speciality services: bronchoscopy, endoscopy, interventional cardiology, and interventional radiology. Events were defined as provided by the World Society of Intravenous Anaesthesia. One thousand four hundred one patients were enrolled in the evaluation, with 666 patients before and 735 after implementation of capnography. Data was entered as a convenience sample on site in an offline data-collection tool. Results were assessed for the relative reduction in the incidence and resulting adjusted odds ratio for the combined incidence of oxygen desaturation (75-90% for <60s), severe oxygen desaturation (<75% at any time) or prolonged oxygen desaturation (<90% for >60s), bradycardia (>25% from baseline) and tachycardia (>25% from baseline). The adjusted odds ratio was controlled for both procedure and patient characteristics. Results: After implementation of capnography, a significant reduction (43.2%, p ≤ 0.05) in adverse events was observed: 147 adverse events occurred during 666 procedures without capnography compared with 93 adverse events that occurred during 735 procedures with capnography. The adjusted odds ratio for the occurrence of the target adverse events was 0.57 (95% CI: 0.42-0.77). Multivariable linear regression indicated that capnography was a significant predictor (p 0.001) of reduced adverse events. Conclusion: These results suggest improved patient safety following capnography implementation.

Corrigendum: Service evaluation of the impact of capnography on the safety of procedural sedation.

[This corrects the article DOI: 10.3389/fmed.2022.867536.].

Remotely Monitored Cardiac Implantable Electronic Device Data Predict All-Cause and Cardiovascular Unplanned Hospitalization.

Background Unplanned hospitalizations are common in patients with cardiovascular disease. The "Triage Heart Failure Risk Status" (Triage-HFRS) algorithm in patients with cardiac implantable electronic devices uses data from up to 9 device-derived physiological parameters to stratify patients as low/medium/high risk of 30-day heart failure (HF) hospitalization, but its use to predict all-cause hospitalization has not been explored. We examined the association between Triage-HFRS and risk of all-cause, cardiovascular, or HF hospitalization. Methods and Results A prospective observational study of 435 adults (including patients with and without HF) with a Medtronic Triage-HFRS-enabled cardiac implantable electronic device (cardiac resynchronization therapy device, implantable cardioverter-defibrillator, or pacemaker). Cox proportional hazards models explored association between Triage-HFRS and time to hospitalization; a frailty term at the patient level accounted for repeated measures. A total of 274 of 435 patients (63.0%) transmitted ≥1 high HFRS transmission before or during the study period. The remaining 161 patients never transmitted a high HFRS. A total of 153 (32.9%) patients had ≥1 unplanned hospitalization during the study period, totaling 356 nonelective hospitalizations. A high HFRS conferred a 37.3% sensitivity and an 86.2% specificity for 30-day all-cause hospitalization; and for HF hospitalizations, these numbers were 62.5% and 85.6%, respectively. Compared with a low Triage-HFRS, a high HFRS conferred a 4.2 relative risk of 30-day all-cause hospitalization (8.5% versus 2.0%), a 5.0 relative risk of 30-day cardiovascular hospitalization (3.6% versus 0.7%), and a 7.7 relative risk of 30-day HF hospitalization (2.0% versus 0.3%). Conclusions In patients with cardiac implantable electronic devices, remotely monitored Triage-HFRS data discriminated between patients at high and low risk of all-cause hospitalization (cardiovascular or noncardiovascular) in real time.

Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity.

Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the "anti-proteinase" molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.

Proteoglycan 4 (PRG4) treatment enhances wound closure and tissue regeneration.

The wound healing response is one of most primitive and conserved physiological responses in the animal kingdom, as restoring tissue integrity/homeostasis can be the difference between life and death. Wound healing in mammals is mediated by immune cells and inflammatory signaling molecules that regulate tissue resident cells, including local progenitor cells, to mediate closure of the wound through formation of a scar. Proteoglycan 4 (PRG4), a protein found throughout the animal kingdom from fish to elephants, is best known as a glycoprotein that reduces friction between articulating surfaces (e.g. cartilage). Previously, PRG4 was also shown to regulate the inflammatory and fibrotic response. Based on this, we asked whether PRG4 plays a role in the wound healing response. Using an ear wound model, topical application of exogenous recombinant human (rh)PRG4 hastened wound closure and enhanced tissue regeneration. Our results also suggest that rhPRG4 may impact the fibrotic response, angiogenesis/blood flow to the injury site, macrophage inflammatory dynamics, recruitment of immune and increased proliferation of adult mesenchymal progenitor cells (MPCs) and promoting chondrogenic differentiation of MPCs to form the auricular cartilage scaffold of the injured ear. These results suggest that PRG4 has the potential to suppress scar formation while enhancing connective tissue regeneration post-injury by modulating aspects of each wound healing stage (blood clotting, inflammation, tissue generation and tissue remodeling). Therefore, we propose that rhPRG4 may represent a potential therapy to mitigate scar and improve wound healing.

Exploratory cost-effectiveness model of electromagnetic navigation bronchoscopy (ENB) compared with CT-guided biopsy (TTNA) for diagnosis of malignant indeterminate peripheral pulmonary nodules.

INTRODUCTION: Lung cancer is accountable for 35 000 deaths annually, and prognosis is improved when the cancer is diagnosed early. CT-guided biopsy (transthoracic needle aspiration, TTNA) and electromagnetic navigation bronchoscopy (ENB) can be used to investigate indeterminate pulmonary nodules if the patient is unfit for surgery. However, there is a paucity of clinical and health economic evidence that directly compares ENB with TTNA in this population group. This cost-effectiveness study aimed to explore potential scenarios whereby ENB may be considered cost-effective when compared with TTNA. METHODS: A cohort decision analytic model was developed using a UK National Health Service perspective. ENB was assumed to have equal sensitivity to TTNA at 82%. Lifetime costs and quality-adjusted life-year (QALY) gain were calculated to estimate the net monetary benefit at a £20 000 per QALY threshold. Sensitivity analyses were used to explore scenarios where ENB could be considered a cost-effective intervention. RESULTS: Under the assumption that ENB has equal efficacy to TTNA, ENB was found to be dominant (less costly and more effective) when compared with TTNA, due to having a reduced risk and cost of adverse events. This conclusion was most sensitive to changes in the cost of intervention, estimates of effectiveness and adverse event rates. DISCUSSION: ENB is expected to be cost-effective when the likelihood of an accurate diagnosis is equal to (or better than) TTNA, which may occur in certain subgroups of patients in whom TTNA is unlikely to accurately diagnose malignancy or when an experienced practitioner achieves a high accuracy with ENB.

The cost-effectiveness of radiofrequency ablation for treating patients with gastric antral vascular ectasia refractory to first line endoscopic therapy.

Objective: This economic evaluation aims to provide a preliminary assessment of the cost-effectiveness of radiofrequency ablation (RFA) compared with argon plasma coagulation (APC) when used to treat APC-refractory gastric antral vascular ectasia (GAVE) in symptomatic patients.Methods: A Markov model was constructed to undertake a cost-utility analysis for adults with persistent symptoms secondary to GAVE refractory to first line endoscopic therapy. The economic evaluation was conducted from a UK NHS and personal social services (PSS) perspective, with a 20-year time horizon, comparing RFA with APC. Patients transfer between health states defined by haemoglobin level. The clinical effectiveness data were sourced from expert opinion, resource use and costs were reflective of the UK NHS and benefits were quantified using Quality Adjusted Life Years (QALYs) with utility weights taken from the literature. The primary output was the Incremental Cost-Effectiveness Ratio (ICER), expressed as cost per QALY gained.Results: Over a lifetime time horizon, the base case ICER was £4840 per QALY gained with an 82.2% chance that RFA was cost-effective at a threshold of £20,000 per QALY gained. The model estimated that implementing RFA would result in reductions in the need for intravenous iron, endoscopic intervention and requirement for blood transfusions by 27.1%, 32.3% and 36.5% respectively. Compared to APC, RFA was associated with an estimated 36.7% fewer procedures.Conclusions: RFA treatment is likely to be cost-effective for patients with ongoing symptoms following failure of first line therapy with APC and could lead to substantive reductions in health care resource.

Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis.

Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclusively expressing the Pro260 variant of SPTA1 and her mother (pElm), heterozygous for this mutation. At the molecular level, the pEI RBC proteome was globally preserved but spectrin density at cell edges was increased. Decreased phosphatidylserine vs. increased lysophosphatidylserine species, and enhanced lipid peroxidation, methemoglobin, and plasma acid sphingomyelinase (aSMase) activity were observed. At the biophysical level, although membrane transversal asymmetry was preserved, curvature at RBC edges and rigidity were increased. Lipid domains were altered for membrane:cytoskeleton anchorage, cholesterol content and response to Ca2+ exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca2+ exchanges. The contribution of increased membrane curvature to the pEl phenotype was shown by mechanistic experiments in healthy RBCs upon lysophosphatidylserine membrane insertion. The role of lipid domain defects was proved by cholesterol depletion and aSMase inhibition in pEl. The data indicate that aberrant membrane content and biophysical properties alter pEl RBC morphology and functionality.

CCL2 But Not CCR2 Is Required for Spontaneous Articular Cartilage Regeneration Post-Injury.

The role of the inflammatory response in articular cartilage degeneration and/or repair is often debated. Chemokine networks play a critical role in directing the recruitment of immune cells to sites of injury and have been shown to regulate cell behavior. In this study, we investigated the role of the CCL2/CCR2 signaling axis in cartilage regeneration and degeneration. CCL2-/- , CCR2-/- , CCL2-/- CCR2-/- , and control (C57) mice were subjected to full-thickness cartilage defect (FTCD) injuries (n = 9/group) within the femoral groove. Cartilage regeneration at 4 and 12 weeks post-FTCD was assessed using a 14-point histological scoring scale. Mesenchymal stem cells (MSCs) (Sca-1+ , CD140a+ ), macrophages (M1:CD38+ , M2:CD206+ , and M0:F4/80+ ) and proliferating cells (Ki67+ ) were quantified within joints using immunofluorescence. The multi-lineage differentiation capacity of Sca1+ MSCs was determined for all mouse strains. ACL transection (ACL-x) was employed to determine if CCL2-/- CCR2-/- mice were protected against osteoarthritis (OA) (n = 6/group). Absence of CCR2, but not CCL2 nor both (CCL2 and CCR2), enhanced spontaneous articular cartilage regeneration by 4 weeks post-FTCD. Furthermore, increased chondrogenesis was observed in MSCs derived from CCR2-/- mice. CCL2 deficiency promoted MSC homing to the adjacent synovium and FTCD at both 4 and 12 weeks post-injury; with no MSCs present at the surface of the FTCD in the remaining strains. Lower OA scores were observed in CCL2-/- CCR2-/- mice at 12 weeks post-ACL-x compared with C57 mice. Our findings demonstrate an inhibitory role for CCR2 in cartilage regeneration after injury, while CCL2 is required for regeneration, acting through a CCR2 independent mechanism. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2561-2574, 2019.

A cost-effectiveness analysis of endoscopic eradication therapy for management of dysplasia arising in patients with Barrett's oesophagus in the United Kingdom.

BACKGROUND AND AIMS: Endoscopic eradication therapy (EET) is the first line approach for treating Barrett's oesophagus (BE) related neoplasia globally. The British Society of Gastroenterology (BSG) recommend EET with combined endoscopic resection (ER) for visible dysplasia followed by endoscopic ablation in patients with both low and high grade dysplasia (LGD and HGD). The aim of this study is to perform a cost-effectiveness analysis for EET for treatment of all grades of dysplasia in BE patients. METHODS: A Markov cohort model with a lifetime time horizon was used to undertake a cost-effectiveness analysis. A hypothetical cohort of UK patients diagnosed with BE entered the model. Patients in the treatment arm with LGD and HGD received EET and patients with non-dysplastic BE (NDBE) received endoscopic surveillance only. In the comparator arm, patients with LGD, HGD and NDBE received endoscopic surveillance only. A UK National Health Service (NHS) perspective was adopted and the incremental cost-effectiveness ratio (ICER) was calculated. Sensitivity analysis was conducted on key input parameters. RESULTS: EET for patients with LGD and HGD arising in BE is cost-effective compared to endoscopic surveillance alone (lifetime ICER £3006 per quality adjusted life year [QALY] gained). The results show that, as the time horizon increases, the treatment becomes more cost-effective. The 5 year financial impact to the UK NHS of introducing EET is £7.1m. CONCLUSIONS: EET for patients with low and high grade BE dysplasia, following updated guidelines from the BSG, has been shown to be cost-effective for patients with BE in the UK.