The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Doping of casted silk fibroin membranes with extracellular vesicles for regenerative therapy: a proof of concept.

Bioactive material concepts for targeted therapy have been an important research focus in regenerative medicine for years. The aim of this study was to investigate a proof-of-concept composite structure in the form of a membrane made of natural silk fibroin (SF) and extracellular vesicles (EVs) from gingival fibroblasts. EVs have multiple abilities to act on their target cell and can thus play crucial roles in both physiology and regeneration. This study used pH neutral, degradable SF-based membranes, which have excellent cell- and tissue-specific properties, as the carrier material. The characterization of the vesicles showed a size range between 120 and 180 nm and a high expression of the usual EV markers (e.g. CD9, CD63 and CD81), measured by nanoparticle tracking analysis (NTA) and single-EV flow analysis (IFCM). An initial integration of the EVs into the membrane was analyzed using scanning and transmission electron microscopy (SEM and TEM) and vesicles were successfully detected, even if they were not homogeneously distributed in the membrane. Using direct and indirect tests, the cytocompatibility of the membranes with and without EVs could be proven and showed significant differences compared to the toxic control (p < 0.05). Additionally, proliferation of L929 cells was increased on membranes functionalized with EVs (p > 0.05).

Knockout of bone sialoprotein in cementoblasts cell lines affects specific gene expression in unstimulated and mechanically stimulated conditions.

One of the major components in cementum extracellular matrix is bone sialoprotein (BSP). BSP knockout (Ibsp) mice were reported to have a nonfunctional hypo-mineralized cementum, as well as detachment and disorganization of the periodontal ligament tissue. However, studies investigating the influence of Ibsp in cementoblasts are missing yet. This study investigates the influences of Bsp in three cementoblasts cell lines (OCCM.30-WT,IbspΔNterm, and IbspKAE). The mRNA expression of cementoblast and osteoclast markers (Col1a1, Alpl, Ocn, Runx2, Ctsk, Rankl and Opg) and the cell morphology were compared. Additionally, a functional monocyte adhesion assay was performed. To understand the influence of external stimuli, the effect of Ibsp was investigated under static compressive force, mimicking the compression side of orthodontic tooth movement. Cementoblasts with genotype IbspΔNterm and IbspKAE showed slight differences in cell morphology compared to OCCM.30-WT, as well as different gene expression. Under compressive force, the Ibsp cell lines presented expression pattern markers similar to the OCCM.30-WT cell line. However, Cathepsin K was strongly upregulated in IbspΔNterm cementoblasts under compressive force. This study provides insight into the role of BSP in cementoblasts and explores the influence of BSP on periodontal ligament tissues. BSP markers in cementoblasts seem to be involved in the regulation of cementum organization as an important factor for a functional periodontium. In summary, our findings provide a basis for investigations regarding molecular biology interactions of BSP in cementoblasts, and a supporting input for understanding the periodontal and cellular cementum remodeling.

Long-Term Degradation Assessment of a Polyurethane-Based Surgical Adhesive-Assessment and Critical Consideration of Preclinical In Vitro and In Vivo Testing.

Tissue adhesives constitute a great possibility to improve conventional wound closure. In contrast to sutures, they enable nearly immediate hemostasis and can prevent fluid or air leaks. In the present study, a poly(ester)urethane-based adhesive was investigated which already proved to be suitable for different indications, such as reinforcing vascular anastomosis and sealing liver tissue. Using in vitro and in vivo setups, the degradation of the adhesives was monitored over a period of up to 2 years, to evaluate long-term biocompatibility and determine degradation kinetics. For the first time, the complete degradation of the adhesive was documented. In subcutaneous locations, tissue residues were found after 12 months and in intramuscular locations, tissue degradation was complete after about 6 months. A detailed histological evaluation of the local tissue reaction revealed good biocompatibility throughout the different degradation stages. After full degradation, complete remodeling to physiological tissue was observed at the implant locations. In addition, this study critically discusses common issues related to the assessment of biomaterial degradation kinetics in the context of medical device certification. This work highlighted the importance and encouraged the implementation of biologically relevant in vitro degradation models to replace animal studies or at least reduce the number of animals in preclinical testing prior to clinical studies. Moreover, the suitability of frequently used implantation studies based on ISO 10993-6 at standard locations was critically discussed, especially in light of the associated lack of reliable predictions for degradation kinetics at the clinically relevant site of implantation.

A systematic review of the cost-effectiveness of renal replacement therapies, and consequences for decision-making in the end-stage renal disease treatment pathway.

OBJECTIVES: Comparative economic assessments of renal replacement therapies (RRT) are common and often used to inform national policy in the management of end-stage renal disease (ESRD). This study aimed to assess existing cost-effectiveness analyses of dialysis modalities and consider whether the methods applied and results obtained reflect the complexities of the real-world treatment pathway experienced by ESRD patients. METHODS: A systematic literature review (SLR) was conducted to identify cost-effectiveness studies of dialysis modalities from 2005 onward by searching Embase, MEDLINE, EBM reviews, and EconLit. Economic evaluations were included if they compared distinct dialysis modalities (e.g. in-centre haemodialysis [ICHD], home haemodialysis [HHD] and peritoneal dialysis [PD]). RESULTS: In total, 19 cost-effectiveness studies were identified. There was considerable heterogeneity in perspectives, time horizon, discounting, utility values, sources of clinical and economic data, and extent of clinical and economic elements included. The vast majority of studies included an incident dialysis patient population. All studies concluded that home dialysis treatment options were cost-effective interventions. CONCLUSIONS: Despite similar findings across studies, there are a number of uncertainties about which dialysis modalities represent the most cost-effective options for patients at different points in the care pathway. Most studies included an incident patient cohort; however, in clinical practice, patients may switch between different treatment modalities over time according to their clinical need and personal circumstances. Promoting health policies through financial incentives in renal care should reflect the cost-effectiveness of a comprehensive approach that considers different RRTs along the patient pathway; however, no such evidence is currently available.

Antimicrobial efficiency and cytocompatibility of different decontamination methods on titanium and zirconium surfaces.

OBJECTIVES: The purpose of this study was to investigate the efficiency of different implant-decontamination methods regarding biofilm modification and potential cytotoxic effects. Therefore, the amount of biofilm reduction, cytocompatibility, and elementary surface alterations were evaluated after decontamination of titanium and zirconium surfaces. MATERIAL AND METHODS: Titanium and zirconium disks were contaminated with a newly developed high-adherence biofilm consisting of six microbial species. Decontaminations were performed using titanium curette, stainless steel ultrasonic scaler (US), glycine (GPAP) and erythritol (EPAP) powder air-polishing, Er:YAG laser, 1% chlorhexidine (CHX), 10% povidone-iodine (PVI), 14% doxycycline (doxy), and 0.95% NaOCl solution. Microbiologic analysis was done using real-time qPCR. For assessment of cytocompatibility, a multiplex assay for the detection of cytotoxicity, viability, and apoptosis on human gingival fibroblasts was performed. X-ray photoelectron spectroscopy (XPS) was used to evaluate chemical alterations on implant surfaces. RESULTS: Compared with untreated control disks, only GPAP, EPAP, US, and Er:YAG laser significantly reduced rRNA counts (activity) on titanium and zirconium (p < .01), whereas NaOCl decreased rRNA count on titanium (p < .01). Genome count (bacterial presence) was significantly reduced by GPAP, EPAP, and US on zirconium only (p < .05). X-ray photoelectron spectroscopy analyses revealed relevant re-exposure of implant surface elements after GPAP, EPAP, and US treatment on both materials, however, not after Er:YAG laser application. Cytocompatibility was impaired by CHX, PVI, doxy, and NaOCl. CHX and PVI resulted in the lowest viability and doxy in the highest apoptosis. CONCLUSIONS: Within the limits of this in vitro study, air-polishing methods and ultrasonic device resulted in effective biofilm inactivation with surface re-exposure and favorable cytocompatibility on titanium and zirconium. Chemical agents, when applied on implant surfaces, may cause potential cytotoxic effects.

Cardiovascular Risk Profiles and Pre-Existing Health Conditions of Trekkers in the Solu-Khumbu Region, Nepal.

BACKGROUND: High-altitude tourist trekking continues to grow in popularity on the Everest Trek in Nepal. We examined which pre-existing cardiovascular and health conditions these global trekkers had and what health issues they encountered during the trek, be it exacerbations of pre-existing conditions, or new acute ones. METHOD: Trekkers (n = 350) were recruited from guesthouses along the Everest Trek, mostly at Tengboche (3860 m). After completing a questionnaire on their health and travel preparation, they underwent a basic physical examination with an interview. RESULTS: Almost half (45%) had pre-existing conditions, mostly orthopaedic and cardiovascular diseases. The average age was 42.7 years (range 18-76). The average BMI was 23.4 kg/m2, but 21% were overweight. A third were smokers (30%), and 86% had at least one major cardiovascular risk factor. A quarter (25%) were suffering from manifest acute mountain sickness (AMS), and 72% had at least one symptom of AMS. Adequate pre-travel examination, consultation, and sufficient personal preparation were rarely found. In some cases, a distinct cardiovascular risk profile was assessed. Hypertensive patients showed moderately elevated blood pressure, and cholesterol levels were favourable in most cases. No cardiovascular emergencies were found, which was fortunate as timely, sufficient care was not available during the trek. CONCLUSION: The results of earlier studies in the Annapurna region should be revalidated. Every trekker to the Himalayas should consult a physician prior to departure, ideally a travel medicine specialist. Preventative measures and education on AMS warrant special attention. Travellers with heart disease or with a pronounced cardiovascular risk profile should be presented to an internal medicine professional. Travel plans must be adjusted individually, especially with respect to adequate acclimatisation time and no physical overloading. With these and other precautions, trekking at high altitudes is generally safe and possible, even with significant pre-existing health conditions. Trekking can lead to invaluable personal experiences. Since organized groups are limited in their flexibility to change their itinerary, individual trekking or guided tours in small groups should be preferred.

Companion Rescue and Risk Management of Trekkers on the Everest Trek, Solo Khumbu Region, Nepal.

BACKGROUND: Trekking to high-altitude locations presents inherent health-related hazards, many of which can managed with specific first aid (FA) training. This study evaluates the trip preparation, FA knowledge, and FA self-assessment of trekkers (organized by tour operators vs. individually planned tours). Data obtained shall be used for specific FA trip preparation and management of emergencies en route for this population. METHODS: A total of 366 trekkers on the Everest Base Camp Trek, Nepal, were interviewed using a questionnaire specifically designed to evaluate their FA knowledge and management of emergencies. Data evaluation was performed using descriptive statistics. RESULTS: A total of 40.5% of trekkers experienced at least one medical incident during their trip, of which almost 50% were due to acute mountain sickness (AMS). There was more AMS in commercially organized groups than in individually planned ones (55% vs. 40%). For more than 50%, no medical care was available during their trip. A total of 80% could answer only 3/21 FA questions completely correctly. Only 1% showed adequate knowledge concerning FA strategies. A total of 70% were willing to enroll in an FA class specialized towards the needs of trekkers. CONCLUSIONS: The importance of high-altitude FA knowledge and trip preparation is widely underestimated. There is an unmet demand amongst trekkers for specific wilderness FA classes.

Variables Influencing the Pressure and Volume of the Pulmonary Circulation as Risk Factors for Developing High Altitude Pulmonary Edema (HAPE).

BACKGROUND: At altitudes above 2500 m, the risk of developing high altitude pulmonary edema (HAPE) grows with the increases in pulmonary arterial pressure. HAPE is characterized by severe pulmonary hypertension, though the incidence and relevance of individual risk factors are not yet predictable. However, the systolic pulmonary pressure (SPAP) and peak in tricuspid regurgitation velocity (TVR) are crucial factors when diagnosing pulmonary hypertension by echocardiography. METHODS: The SPAP and TVR of 27 trekkers aged 20-65 years en route to the Solu Khumbu region of Nepal were assessed. Echocardiograph measurements were performed at Lukla (2860 m), Gorak Shep (5170 m), and the summit of Kala Patthar (5675 m). The altitude profile and the participants' characteristics were also compiled for correlation with the measured data. RESULTS: The results showed a highly significant increase in SPAP and TVR after ascending Kala Patthar. The study revealed a lower increase of SPAP and TVR in the group of older participants, although the respective initial measurements at Gorak Shep were significantly higher for this group. A similar finding occurred in those using Diamox® as prophylaxis. There was an inverse relationship between TVR and SPAP, the peripheral capillary oxygen saturation, and heart rate. CONCLUSIONS: The echocardiograph results indicated that older people are an at-risk group for developing HAPE. A conservative interpretation of the basic tactical rules for altitudes should be followed for older trekkers or trekkers with known problems of altitude acclimatization ("slow acclimatizer") as SPAP elevates with age. The prophylactic use of Acetazolamide (Diamox®) should be avoided where not necessary for acute medical reasons. Acetazolamide leads to an increase of SPAP, and this may potentially enhance the risk of developing HAPE. Arterial oxygen saturation measurements can provide an indicator for the self-assessment for the risk of developing HAPE and a rule of thumb for the altitude profile, but does not replace a HAPE diagnosis. Backpack weight, sex, workload (actual ascent speed), and pre-existing diseases were not statistically significant factors related to SPAP and TVR (p ≤ 0.05).

From In Vitro to Perioperative Vascular Tissue Engineering: Shortening Production Time by Traceable Textile-Reinforcement.

BACKGROUND: The production of tissue-engineered vascular graft (TEVG) usually involves a prolonged bioreactor cultivation period of up to several weeks to achieve maturation of extracellular matrix and sufficient mechanical strength. Therefore, we aimed to substantially shorten this conditioning time by combining a TEVG textile scaffold with a recently developed copolymer reinforced fibrin gel as a cell carrier. We further implemented our grafts with magnetic resonance imaging (MRI) contrast agents to allow the in-vitro monitoring of the TEVG's remodeling process. METHODS: Biodegradable polylactic-co-glycolic acid (PLGA) was electrospun onto a non-degradable polyvinylidene fluoride scaffold and molded along with copolymer-reinforced fibrin hydrogel and human arterial cells. Mechanical tests on the TEVGs were performed both instantly after molding and 4 days of bioreactor conditioning. The non-invasive in vitro monitoring of the PLGA degradation and the novel imaging of fluorinated thermoplastic polyurethane (19F-TPU) were performed using 7T MRI. RESULTS: After 4 days of close loop bioreactor conditioning, 617 ± 85 mmHg of burst pressure was achieved, and advanced maturation of extracellular matrix (ECM) was observed by immunohistology, especially in regards to collagen and smooth muscle actin. The suture retention strength (2.24 ± 0.3 N) and axial tensile strength (2.45 ± 0.58 MPa) of the TEVGs achieved higher values than the native arteries used as control. The contrast agents labeling of the TEVGs allowed the monitorability of the PLGA degradation and enabled the visibility of the non-degradable textile component. CONCLUSION: Here, we present a concept for a novel textile-reinforced TEVG, which is successfully produced in 4 days of bioreactor conditioning, characterized by increased ECM maturation and sufficient mechanical strength. Additionally, the combination of our approach with non-invasive imaging provides further insights into TEVG's clinical application.

Analysis of local drinking water for fecal contamination in Solu-Khumbu / Mt. Everest region, Nepal.

BACKGROUND: To evaluate the drinking water quality in the popular trekking area of Solu-Khumbu Mt. Everest region as a possible source for the high incidence of diarrhea. MATERIAL AND METHODS: Drinking water samples (n = 80) were collected from whatever primary source the locals/tourists used at altitudes 2,608 to 5,180m; and where possible, also from inside households. Samples were analyzed for fecal contamination using the DelAgua Dual Incubator at 37 °C and 44 °C to detect the total and thermotolerant coliform bacteria. The pH, temperature, turbidity, smell, and taste were also registered. RESULTS: No thermotolerant bacteria were found but a significant number of specimens contained many colony forming units (CFU) of total coliform bacteria. Household specimens were more often contaminated compared to the water from the primary source. CONCLUSION: Data indicate a significant secondary contamination when water was handled and stored in unhygienic containers. Health education programs on water hygiene, sanitation, and the safe handling and storage of water needs improvement. It is strongly recommended that drinking water is disinfected using filter systems, UV-light dispensers or halogens (e.g. chlorine), or a combination of two methods. Although cooking is a common disinfection method here, fuel is scarce. Water was generally safer when collected directly from the primary source in a clean container than from a lodge.

Main Barriers to the Introduction of a Home Haemodialysis Programme in Poland: A Review of the Challenges for Implementation and Criteria for a Successful Programme.

INTRODUCTION: Home dialysis in Poland is restricted to the peritoneal dialysis (PD) modality, with the majority of dialysis patients treated using in-centre haemodialysis (ICHD). Home haemodialysis (HHD) is an additional home therapy to PD and provides an attractive alternative to ICHD that combines dialysis with social distancing; eliminates transportation needs; and offers clinical, economic, and quality of life benefits. However, HHD is not currently provided in Poland. This review was performed to provide an overview of the main barriers to the introduction of a HHD programme in Poland. MAIN FINDINGS: The main high-level barrier to introducing HHD in Poland is the absence of specific health legislation required for clinician prescribing of HHD. Other barriers to overcome include clear definition of reimbursement, patient training and education (including infrastructure and experienced personnel), organisation of logistics, and management of complications. Partnering with a large care network for HHD represents an alternative option to payers for the provision of a new HHD service. This may reduce some of the barriers which need to be overcome when compared with the creation of a new HHD service and its supporting network due to the pre-existing infrastructure, processes, and staff of a large care network. CONCLUSIONS: Provision of HHD is not solely about the provision of home treatment, but also the organisation and definition of a range of support services that are required to deliver the service. HHD should be viewed as an additional, complementary option to existing dialysis modalities which enables choice of modality best suited to a patient's needs.

Switching from high-flux dialysis to hemodiafiltration: Cost-consequences for patients, providers, and payers.

Hemodiafiltration (HDF) achieves a more efficient reduction of the uremic toxic load compared to standard high-flux hemodialysis (HF-HD) by virtue of the combined diffusive and convective clearances of a broad spectrum of uremic retention solutes. Clinical trials and registry data suggest that HDF improves patient outcomes. Despite the acknowledged need to improve survival rates of dialysis patients and the survival benefit HDF offers, there is little to no utilization in some countries (such as the US) in prescribing HDF to their patients. In this analysis, we present the healthcare value-based case for HDF (relative to HF-HD) from the patient, provider, and payor perspectives. The improved survival and reduced morbidity observed in studies conducted outside the US, as well as the reduced hospitalization, are attractive for each stakeholder. We also consider the potential barriers to greater utilization of HDF therapies, including unfounded concerns regarding additional costs of HDF, e.g., for the preparation and microbial testing of quality of substitution fluids. Ultrapure fluids are easily attainable and prepared from dialysis fluids using established "online" (OL) technologies. OL-HDF has matured to a level whereby little additional effort is required to safely implement it as all modern machine systems are today equipped with the OL-HDF functionality. Countries already convinced of the advantages of HF-HD are thus well positioned to make the transition to OL-HDF to achieve further clinical and associated economic benefits. Healthcare systems struggling to cope with the increasing demand for HD therapies would therefore, like patients, be beneficiaries in the long term with increased usage of OL-HDF for end stage kidney disease patients.

A polyurethane-based surgical adhesive for sealing blood vessel anastomoses-A feasibility study in pigs.

Peri- and postoperative anastomotic leakage from blood vessel anastomosis is a common and potentially life-threatening complication. As an adjunctive therapy providing an additional layer of safety, a new biodegradable, polyurethane-based adhesive was developed. It consists of two components: an isocyanate-functionalized prepolymer and an amino-based curing agent. The adhesive was investigated in a porcine animal model to seal sutured blood vessel anastomoses of arteries, veins, aortas and prosthetic aortic graft replacements. The material-determined properties of the adhesive like viscosity, processing and polymerization time as well as bonding strength were well suited for this application. The adhesive stopped perioperative suture-line bleedings and stayed on all anastomoses until sacrifice. Hematological and serological inflammation marker assessments were unobtrusive. The histological evaluation showed a mild to moderate local tissue reaction to the adhesive constituting a physiological, non-adverse tissue-biomaterial interaction. The adhesive did not interfere with vascular wound healing. The adhesive demonstrated to be suitable to improve the outcome of cardiovascular surgeries by securing the classical sutured anastomoses in a fast, easy and safe manner. However, further studies are required to quantitatively evaluate efficacy in terms of anastomotic leakage prevention as well as long-term tissue compatibility and degradation.

Monitoring the Remodeling of Biohybrid Tissue-Engineered Vascular Grafts by Multimodal Molecular Imaging.

Tissue-engineered vascular grafts (TEVGs) with the ability to grow and remodel open new perspectives for cardiovascular surgery. Equipping TEVGs with synthetic polymers and biological components provides a good compromise between high structural stability and biological adaptability. However, imaging approaches to control grafts' structural integrity, physiological function, and remodeling during the entire transition between late in vitro maturation and early in vivo engraftment are mandatory for clinical implementation. Thus, a comprehensive molecular imaging concept using magnetic resonance imaging (MRI) and ultrasound (US) to monitor textile scaffold resorption, extracellular matrix (ECM) remodeling, and endothelial integrity in TEVGs is presented here. Superparamagnetic iron-oxide nanoparticles (SPION) incorporated in biodegradable poly(lactic-co-glycolic acid) (PLGA) fibers of the TEVGs allow to quantitatively monitor scaffold resorption via MRI both in vitro and in vivo. Additionally, ECM formation can be depicted by molecular MRI using elastin- and collagen-targeted probes. Finally, molecular US of αv ß3 integrins confirms the absence of endothelial dysfunction; the latter is provocable by TNF-α. In conclusion, the successful employment of noninvasive molecular imaging to longitudinally evaluate TEVGs remodeling is demonstrated. This approach may foster its translation from in vitro quality control assessment to in vivo applications to ensure proper prostheses engraftment.

Performance-based risk-sharing agreements in renal care: current experience and future prospects.

INTRODUCTION: Performance-based risk-sharing agreements (PBRSAs), between payers, health care providers, and technology manufacturers can be useful when there is uncertainty about the (cost-) effectiveness of a new technology or service. However, they can be challenging to design and implement. AREAS COVERED: A total of 18 performance-based agreements were identified through a literature review. All but two of the agreements identified were pay-for-performance schemes, agreed between providers and payers at the national level. No examples were found of agreements between health care providers and manufacturers at the local level. The potential for these local agreements was illustrated by hypothetical case studies of water quality management and an integrated chronic kidney disease program. EXPERT OPINION: Performance-based risk-sharing agreements can work to the advantage of patients, health care providers, payers, and technology manufacturers, particularly if they facilitate the introduction of technologies or systems of care that might not have been introduced otherwise. However, the design, conduct, and implementation of PBRSAs in renal care pose a number of challenges. Efforts should be made to overcome these challenges so that more renal care patients can benefit from technological advances and new models of care.

Informed decision-making in delivery of dialysis: combining clinical outcomes with sustainability.

As the prevalence of chronic kidney disease is expected to rise worldwide over the next decades, provision of renal replacement therapy (RRT), will further challenge budgets of all healthcare systems. Most patients today requiring RRT are treated with haemodialysis (HD) therapy and are elderly. This article demonstrates the interdependence of clinical and sustainability criteria that need to be considered to prepare for the future challenges of delivering dialysis to all patients in need. Newer, more sustainable models of high-value care need to be devised, whereby delivery of dialysis is based on value-based healthcare (VBHC) principles, i.e. improving patient outcomes while restricting costs. Essentially, this entails maximizing patient outcomes per amount of money spent or available. To bring such a meaningful change, revised strategies having the involvement of multiple stakeholders (i.e. patients, providers, payers and policymakers) need to be adopted. Although each stakeholder has a vested interest in the value agenda often with conflicting expectations and motivations (or motives) between each other, progress is only achieved if the multiple blocs of the delivery system are advanced as mutually reinforcing entities. Clinical considerations of delivery of dialysis need to be based on the entire patient disease pathway and evidence-based medicine, while the non-clinical sustainability criteria entail, in addition to economics, the societal and ecological implications of HD therapy. We discuss how selection of appropriate modes and features of delivery of HD (e.g. treatment modalities and schedules, selection of consumables, product life cycle assessment) could positively impact decision-making towards value-based renal care. Although the delivery of HD therapy is multifactorial and complex, applying cost-effectiveness analyses for the different HD modalities (conventional in-centre and home HD) can support in guiding payability (balance between clinical value and costs) for health systems. For a resource intensive therapy like HD, concerted and fully integrated care strategies need to be urgently implemented to cope with the global demand and burden of HD therapy.

Demineralization Inhibitory Effects of Highly Concentrated Fluoride Dentifrice and Fluoride Gels/Solutions on Sound Dentin and Artificial Dentin Caries Lesions in vitro.

OBJECTIVES: The aim of this in vitro study was to compare the demineralization inhibitory effect of gels/solutions used in combination with either standard or highly fluoridated dentifrices on sound dentin as well as on artificial dentin caries-like lesions. METHODS: Bovine dentin specimens (n = 240) with two different surfaces each (sound [ST] and artificial caries lesion [DT]) were prepared and randomly allocated to twelve groups. Weekly interventions during pH-cycling (28 days, 6 × 120 min demineralization/day) were: the application of gels/solutions containing amine fluoride/sodium fluoride (12,500 ppm F [ppm]; pH = 4.4; AmF); NaF (12,500 ppm; pH = 6.6; NaF1); NaF (12,500 ppm; pH = 6.3; NaF2); silver diamine fluoride (14,200 ppm; pH = 8.7; SDF); acidulated phosphate fluoride (12,500 ppm; pH = 3.8; APF), and no intervention (standard control; S). Furthermore, half of the specimens in each group were brushed (10 s; twice per day) with dentifrice slurries containing either 1,450 ppm (e.g., AmF1450) or 5,000 ppm (e.g., AmF5000). Differences in integrated mineral loss (ΔΔZ) and lesion depth (ΔLD) were calculated between values before and after pH-cycling using transversal microradiography. RESULTS: After pH-cycling Ss showed significantly increased ΔZDT and LDDT values, indicating further demineralization. In contrast, except for one, all groups including fluoride gels/solutions showed significantly decreased ΔZDT values. Additional use of most fluoride gels/solutions significantly enhanced mineral gain, mainly in the surface area; however, acidic gels/solutions seemed to have negative effects on lesion depths. SIGNIFICANCE: Under the present pH-cycling conditions the highly fluoridated dentifrice significantly reduced caries progression and additional application of nearly all of the fluoride gels/solutions resulted in remineralization. However, there was no difference in the remineralizing capacity of fluoride gels/solutions when used in combination with either standard or highly fluoridated dentifrices.

Extracellular Vesicles-Loaded Fibrin Gel Supports Rapid Neovascularization for Dental Pulp Regeneration.

Rapid vascularization is required for the regeneration of dental pulp due to the spatially restricted tooth environment. Extracellular vesicles (EVs) released from mesenchymal stromal cells show potent proangiogenic effects. Since EVs suffer from rapid clearance and low accumulation in target tissues, an injectable delivery system capable of maintaining a therapeutic dose of EVs over a longer period would be desirable. We fabricated an EV-fibrin gel composite as an in situ forming delivery system. EVs were isolated from dental pulp stem cells (DPSCs). Their effects on cell proliferation and migration were monitored in monolayers and hydrogels. Thereafter, endothelial cells and DPSCs were co-cultured in EV-fibrin gels and angiogenesis as well as collagen deposition were analyzed by two-photon laser microscopy. Our results showed that EVs enhanced cell growth and migration in 2D and 3D cultures. EV-fibrin gels facilitated vascular-like structure formation in less than seven days by increasing the release of VEGF. The EV-fibrin gel promoted the deposition of collagen I, III, and IV, and readily induced apoptosis during the initial stage of angiogenesis. In conclusion, we confirmed that EVs from DPSCs can promote angiogenesis in an injectable hydrogel in vitro, offering a novel and minimally invasive strategy for regenerative endodontic therapy.

Hand-held bioprinting for de novo vascular formation applicable to dental pulp regeneration.

Aim of the study: Deep carious lesions may cause irreversible pulpitis and the current endodontic treatment typically removes the whole dental pulp tissue, which finally reduces lifespan of the teeth. Nowadays, the most frequent treatment is based on removing the infected tissue and filling the root canal with inert synthetic materials. Tissue engineering approaches are important alternatives to the current treatment, because they can potentially maintain the biological function of the tooth instead of sacrificing it.Materials and Methods: In this study, we propose a tissue engineering approach based on a hand-held in situ bioprinting strategy. Our approach enabled bioprinting of cell-loaded collagen-based bioinks with suitable rheological, structural and biological properties, which allowed for vasculogenesis in the root canal.Results: The rheological properties of the bioprintable bioink were measured by oscillatory amplitude sweep testing and were corroborated by macroscopic evaluation after in vitro culture, in which printed bioinks maintained their original form without contraction. Moreover, we showed evidence for successful vasculogenesis in bioprintable bioinks with comparable quality and quantity to control fibrin and collagen non-bioprintable hydrogels.Conclusions: We conclude that hand-held bioprinting holds potential for in situ treatment of dental diseases with successful evidence for vascular tube formation, as an asset for maintenance of the biological function of the tooth.