Astrocyte 3D culture and bioprinting using peptide functionalized hyaluronan hydrogels.

Astrocytes play an important role in the central nervous system, contributing to the development of and maintenance of synapses, recycling of neurotransmitters, and the integrity and function of the blood-brain barrier. Astrocytes are also linked to the pathophysiology of various neurodegenerative diseases. Astrocyte function and organization are tightly regulated by interactions mediated by the extracellular matrix (ECM). Engineered hydrogels can mimic key aspects of the ECM and can allow for systematic studies of ECM-related factors that govern astrocyte behaviour. In this study, we explore the interactions between neuroblastoma (SH-SY5Y) and glioblastoma (U87) cell lines and human fetal primary astrocytes (FPA) with a modular hyaluronan-based hydrogel system. Morphological analysis reveals that FPA have a higher degree of interactions with the hyaluronan-based gels compared to the cell lines. This interaction is enhanced by conjugation of cell-adhesion peptides (cRGD and IKVAV) to the hyaluronan backbone. These effects are retained and pronounced in 3D bioprinted structures. Bioprinted FPA using cRGD functionalized hyaluronan show extensive and defined protrusions and multiple connections between neighboring cells. Possibilities to tailor and optimize astrocyte-compatible ECM-mimicking hydrogels that can be processed by means of additive biofabrication can facilitate the development of advanced tissue and disease models of the central nervous system.

Bioorthogonally Cross-Linked Hyaluronan-Laminin Hydrogels for 3D Neuronal Cell Culture and Biofabrication.

Laminins (LNs) are key components in the extracellular matrix of neuronal tissues in the developing brain and neural stem cell niches. LN-presenting hydrogels can provide a biologically relevant matrix for the 3D culture of neurons toward development of advanced tissue models and cell-based therapies for the treatment of neurological disorders. Biologically derived hydrogels are rich in fragmented LN and are poorly defined concerning composition, which hampers clinical translation. Engineered hydrogels require elaborate and often cytotoxic chemistries for cross-linking and LN conjugation and provide limited possibilities to tailor the properties of the materials. Here a modular hydrogel system for neural 3D cell cultures, based on hyaluronan and poly(ethylene glycol), that is cross-linked and functionalized with human recombinant LN-521 using bioorthogonal copper-free click chemistry, is shown. Encapsulated human neuroblastoma cells demonstrate high viability and grow into spheroids. Long-term neuroepithelial stem cells (lt-NES) cultured in the hydrogels can undergo spontaneous differentiation to neural fate and demonstrate significantly higher viability than cells cultured without LN. The hydrogels further support the structural integrity of 3D bioprinted structures and maintain high viability of bioprinted and syringe extruded lt-NES, which can facilitate biofabrication and development of cell-based therapies.

Complications and associated healthcare costs of transvenous cardiac pacemakers in Germany.

Aim: This study evaluated the occurrence and associated costs of pacemaker complications in Germany from 2010 to 2013. Patients & methods: Patients with a de novo or replacement implantation of a single or dual chamber pacemaker between 2010 and 2013 were followed for 12 months post-implant using German health insurance claims data. A case-control analysis was performed using propensity score matching to estimate the costs of complications. Results: Out of 12,922 implanted patients, 12.0% had a complication in the year following the implant. Complications related to lead and pocket were found in 10.2% of all implanted patients; infections occurred in 1.7% patients. Healthcare costs up to 36 months post complication were on average €4627 higher than for pacemaker patients without a complication. Conclusion: Pacemaker complications are common and represent a burden for patients and healthcare systems generating substantial costs. Most of the pacemaker complications involved the pacing lead or pacemaker pocket.

Direct medical costs of ADHD and its comorbid conditions on basis of a claims data analysis.

BACKGROUND: ADHD is a highly prevalent disease in childhood which often persists into adulthood, then co-occurring with common adult conditions. Especially for adult ADHD, little is known about the costs of ADHD and the additional costs of comorbid conditions. AIMS: To determine medical costs of ADHD and costs of comorbidities (mood, anxiety and substance use disorders, obesity), including their co-occurrence rates, stratified by age and gender. METHOD: Claims data from a German Statutory Health Insurance database with approximately four million member-records per year were analysed. A total of 25,300 prevalent ADHD patients were identified by means of an ICD-10 GM diagnosis of ADHD. A 1:1 age and gender adjusted reference group without ADHD diagnosis was randomly selected. Total health claims and health care costs related to ADHD were analysed, in addition to more targeted analyses of the occurrence and costs of pre-defined common comorbidities of, in particular, adult ADHD (SUD, mood and anxiety disorders, obesity). Outcomes were mean costs per patient and occurrence rates of comorbid conditions. Surplus costs of a comorbid condition in persons with ADHD relative to costs of this condition in persons without ADHD were calculated. Subgroup analyses were conducted based on age (0-12 years, 13-17 years, 18-30years, 30+ years) and gender. RESULTS: Patients with ADHD were €1500 more expensive annually than individuals without ADHD (p < 0.001). Main cost drivers were inpatient care, psychiatrists and psychotherapists. Mood, anxiety, substance use disorders and obesity were significantly more frequent in ADHD patients and additional costs resulting from the comorbid conditions amounted up to €2800. Costs were slightly higher in women than men and increased with age for both genders. In young adults (18-30 years) health care costs dropped notably, especially costs for the medical treatment of ADHD with stimulants and costs for psychiatrists, before rising again in the group of patients over 30 years who had higher comorbidity rates. CONCLUSIONS: Medical costs for ADHD are substantial, in part through frequently occurring comorbid conditions, and particularly in adulthood, and are likely to further accelerate in the coming years. A gap of care was found, starting with the transition age group of patients over 17 years, as indicated by reduced costs per person during young adulthood, as well as an overall strong drop in administrative prevalence. In the future, approaches to improve the situation of care and reduce costs at the same time, i.e. through managed care programmes, should be implemented and benefit from detailed knowledge on age and gender-specific cost-drivers.

Incidence and costs of cardiac device infections: retrospective analysis using German health claims data.

AIM: Estimate incidence and costs of cardiac device infections (CDIs) in Germany. MATERIALS & METHODS: Patients had an implantable cardioverter defibrillator implanted over 2010-2013 and were followed to December 2014 using German health insurance claims data. A case-controlled analysis was performed using propensity score matching methods. RESULTS: Risk of CDI 12 months post-implant was 3.4% overall, either 2.9% for de novo procedures versus 4.4% for replacement procedures. Mean 3-year incremental expenditure per patient for patients with CDI compared with controls was €31,493 for de novo implant patients and €33,777 for replacement patients. Mean incremental expenditure was €59,419 per patient with a major infection. CONCLUSION: CDIs are highly expensive to manage, reinforcing the need for strategies to reduce their occurrence.

Arbitration Board Setting Reimbursement Amounts for Pharmaceutical Innovations in Germany When Price Negations between Payers and Manufacturers Fail: An Empirical Analysis of 5 Years' Experience.

BACKGROUND: In Germany, an arbitration board is setting reimbursement amounts for drug innovations when price negations between payers and manufacturers fail. OBJECTIVE: To empirically analyze all arbitrations since the reform of Germany's Act to Reorganize the Pharmaceuticals' Market in the Statutory Health Insurance System came into effect. METHODS: All available relevant documents up to January 2016 were screened and the identified contentious issues between the negotiation parties extracted. Reimbursement requests of both the negotiating parties and the arbitrations were transformed into a comparable format on the basis of defined daily doses and then contrasted among each other. RESULTS: In the given period, 16 arbitrations took place. The arbitration board is implementing the same criteria used in the negotiations between manufacturers and payers. Almost all arbitrations dealt with generic appropriate comparative therapies. Reimbursement amounts set by arbitration were on average 38.4% less than the mean of negotiation parties' requests (69.2% less than the manufacturers' requests). The corresponding prescription volumes were arranged rather centrally. All but one arbitration refer to a 1-year contract period. The arbitration board rarely decided on further technical contentious points. Hence, no heuristics referring to them were derivable. CONCLUSIONS: There is some evidence for a quasi-algorithmic approach of the arbitration board, even though it is legally determined that it has to decide while taking the peculiar conditions of each case into due consideration, including the characteristics of the respective therapeutic area. The balance of interests proved to be within a very narrow space albeit it concerns in principle discretionary decisions. Thus, the purpose of arbitration seems not to be achieved sufficiently.