RELEASE-HF study:a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands

Introduction:Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis:The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination:The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible.</p

RELEASE-HF study:a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands

Introduction:Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis:The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination:The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible.</p

Molecular cloning of cat interleukin 12

The recently discovered interleukin-12 (IL-12) is a heterodimeric 70000 Mr cytokine composed of a disulphide-bonded 35000 Mr (p35) subunit and a 40000 Mr (p40) subunit. Produced mainly by activated monocytes/macrophages and B cells, it enhances NK/LAK cell cytolytic activity and stimulates cytotoxic T-cell responses and IFN-γ production. It is therefore a key regulatory molecule in T-helper-cell type-1 (Th-1)-driven immune responses that are considered necessary for the elimination of intracellular pathogens

Molecular cloning of cat interleukin 12

The recently discovered interleukin-12 (IL-12) is a heterodimeric 70000 Mr cytokine composed of a disulphide-bonded 35000 Mr (p35) subunit and a 40000 Mr (p40) subunit. Produced mainly by activated monocytes/macrophages and B cells, it enhances NK/LAK cell cytolytic activity and stimulates cytotoxic T-cell responses and IFN-γ production. It is therefore a key regulatory molecule in T-helper-cell type-1 (Th-1)-driven immune responses that are considered necessary for the elimination of intracellular pathogens

Exacerbated viral hepatitis in IFN γ receptor deficient mice is not suppressed by IL 12

Both IL-12 and IFN-gamma have been implicated as principal inducers of type 1 immune responses required for the elimination of intracellular pathogens, such as viruses. We examined the in vivo antiviral role of both cytokines during coronavirus-induced hepatitis in a mouse hepatitis virus (MHV) model. The absence of IFN-gamma function in mice with a targeted disruption of the IFN-gamma R alpha-chain gene (IFN- gamma R -/-) resulted in increased susceptibility to coronaviral hepatitis associated with augmented viral replication and increased hepatocellular injury. The mutant mice showed a type 1 lymphokine response characterized by the normal high IFN-gamma and low IL-4 production. Unlike MHV-infected wild-type mice, however, the mutant IFN- gamma R -/- mice showed no increase in IL-12 p4O gene expression, similar to that in naive animals. IL-12 treatment failed to restore host resistance in IFN-gamma R -/- mice, but significantly protected MHV-susceptible C57BL/6 mice against lethal infection, although less than IFN-gamma treatment. Mice protected by IL-12 or IFN-gamma showed resistance against an otherwise lethal second MHV infection. Our data demonstrate that despite reduced IL-12 gene expression and defective IFN-gamma R function, virus-induced IFN-gamma production can occur. Furthermore, they emphasize the pivotal antiviral role of IFN-gamma in protection against acute coronavirus-induced hepatitis

Mice lacking IL-12 develop polarized Th1 cells during viral infection

Studies in IL-12-deficient mice established the necessity for IL-12 to generate a Th1 cytokine response that is often required for elimination of intracellular pathogens. In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse hepatitis virus (MHV) infection, similar to wild-type animals. In contrast, MHV-infected IFN- receptor-deficient (IFN-R-/-) mice showed an increased susceptibility to coronaviral hepatitis. Surprisingly, MHV-infected mice lacking IL-12 produced a polarized Th1-type cytokine response, as evidenced by high IFN- and nondetectable IL-4 production by CD4+ splenocytes and normal virus-specific serum IgG2a/IgG1 ratios. The virus-induced type 1 cytokine secretion pattern was not reversed in IL-12-deficient mice by in vivo neutralization of IFN- nor in IFN-R-/- mice receiving IL-12-neutralizing Abs. In IL-12-deficient mice, Th1-type responses were also generated upon immunization with inactivated MHV. In contrast, following immunization with keyhole limpet hemocyanin, mice lacking IL-12 mounted strongly reduced specific IgG2a and increased IgE responses, indicative of a type 2-dominated cytokine pattern. These findings demonstrate that following a virus infection, IL-12 is not essential for the generation of polarized T cell type 1 cytokine expression and associated immune responses, which is in marked contrast to nonviral systems. Our data suggest that viruses may selectively induce IFN- production and Th1-type immune reactions even in the absence of IL-12

Dystrophin deficiency leads to dysfunctional glutamate clearance in iPSC derived astrocytes

Duchenne muscular dystrophy (DMD) results, beside muscle degeneration in cognitive defects. As neuronal function is supported by astrocytes, which express dystrophin, we hypothesized that loss of dystrophin from DMD astrocytes might contribute to these cognitive defects. We generated cortical neuronal and astrocytic progeny from induced pluripotent stem cells (PSC) from six DMD subjects carrying different mutations and several unaffected PSC lines. DMD astrocytes displayed cytoskeletal abnormalities, defects in Ca+2 homeostasis and nitric oxide signaling. In addition, defects in glutamate clearance were identified in DMD PSC-derived astrocytes; these deficits were related to a decreased neurite outgrowth and hyperexcitability of neurons derived from healthy PSC. Read-through molecule restored dystrophin expression in DMD PSC-derived astrocytes harboring a premature stop codon mutation, corrected the defective astrocyte glutamate clearance and prevented associated neurotoxicity. We propose a role for dystrophin deficiency in defective astroglial glutamate homeostasis which initiates defects in neuronal development.Genetics of disease, diagnosis and treatmen