Perceived barriers and facilitators of the implementation of a combined lifestyle intervention with a financial incentive for chronically ill patients

Background  This study aims to describe barriers and facilitators of the implementation of a combined lifestyle intervention (CLI) in primary care for patients with chronic disease. The aim of CLI to help patients to create a healthy lifestyle and to maintain this healthy lifestyle. During a CLI a patient receives advice and counselling to improve health-related behavior such as physical activity and diet. Special attention was given to the influence of adding a health promoting financial incentive (HPFI) for the participants to the CLI.  Methods  Twenty-four semi-structured interviews within six care groups were performed between July and October 2017. The interviews were transcribed verbatim and coded by two researchers independently.  Results  Respondents mentioned several preferred characteristics of the CLI such as easy accessibility of the intervention site and the presence of health care professionals during exercise sessions. Moreover, factors that could influence implementation (such as attitude of the health care professionals) and preconditions for a successful implementation of a CLI (such as structural funding and good infrastructure) were identified. Overall, positive HPFIs (e.g. a reward) were preferred over negative HPFIs (e.g. a fine). According to the respondents, HPFIs could positively influence the degree of participation, and break down barriers for participating in and finishing the CLI.  Conclusions  Multiple barriers and facilitators for successful implementation of a CLI were identified. For successful implementing CLIs, a positive attitude of all stakeholders is essential and specific preconditions should be fulfilled. With regard to adding a HPFI, more research is needed to identify the attitude of specific target groups towards an HPFI

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work-up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence-based recommendations have improved neonatal survival and short-term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post-translational short-chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short-chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising

Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia:What to aim, expect, and evaluate from newborn screening?

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected

Isoscalar giant monopole strength in 58^{58}Ni, 90^{90}Zr, 120^{120}Sn and 208^{208}Pb

Inelastic $\alpha$-particle scattering at energies of a few hundred MeV and very-forward scattering angles including $0^\circ$ has been established as a tool for the study of the isoscalar giant monopole (IS0) strength distributions in nuclei. An independent investigation of the IS0 strength in nuclei across a wide mass range was performed using the $0^\circ$ facility at iThemba Laboratory for Accelerator Based Sciences (iThemba LABS), South Africa, to understand differences observed between IS0 strength distributions in previous experiments performed at the Texas A\&M University (TAMU) Cyclotron Institute, USA and the Research Center for Nuclear Physics (RCNP), Japan. The isoscalar giant monopole resonance (ISGMR) was excited in $^{58}$Ni, $^{90}$Zr, $^{120}$Sn and $^{208}$Pb using $\alpha$-particle inelastic scattering with $196$ MeV $\alpha$ beam and scattering angles $\theta_{\text{Lab}} = 0^\circ$ and $4^\circ$. The K$600$ magnetic spectrometer at iThemba LABS was used to detect and momentum analyze the inelastically scattered $\alpha$ particles. The IS0 strength distributions in the nuclei studied were deduced with the difference-of-spectra (DoS) technique including a correction factor for the $4^\circ$ data based on the decomposition of $L > 0$ cross sections in previous experiments. IS0 strength distributions for $^{58}$Ni, $^{90}$Zr, $^{120}$Sn and $^{208}$Pb are extracted in the excitation-energy region $E_{\rm x} = 9 - 25$ MeV.Using correction factors extracted from the RCNP experiments, there is a fair agreement with their published IS0 results. Good agreement for IS0 strength in $^{58}$Ni is also obtained with correction factors deduced from the TAMU results, while marked differences are found for $^{90}$Zr and $^{208}$Pb.Comment: 12 pages, 10 figures, regular article submitted to PR

Fine structure of the isoscalar giant monopole resonance in 58^{58}Ni, 90^{90}Zr, 120^{120}Sn and 208^{208}Pb

Over the past two decades high energy-resolution inelastic proton scattering studies were used to gain an understanding of the origin of fine structure observed in the isoscalar giant quadrupole resonance (ISGQR) and the isovector giant dipole resonance (IVGDR). Recently, the isoscalar giant monopole resonance (ISGMR) in $^{58}$Ni, $^{90}$Zr, $^{120}$Sn and $^{208}$Pb was studied at the iThemba Laboratory for Accelerator Based Sciences (iThemba LABS) by means of inelastic $\alpha$-particle scattering at very forward scattering angles (including $0\circ$). The good energy resolution of the measurement revealed significant fine structure of the ISGMR.~To extract scales by means of wavelet analysis characterizing the observed fine structure of the ISGMR in order to investigate the role of different mechanisms contributing to its decay width. Characteristic energy scales are extracted from the fine structure using continuous wavelet transforms. The experimental energy scales are compared to different theoretical approaches performed in the framework of quasiparticle random phase approximation (QRPA) and beyond-QRPA including complex configurations using both non-relativistic and relativistic density functional theory. All models highlight the role of Landau fragmentation for the damping of the ISGMR especially in the medium-mass region. Models which include the coupling between one particle-one hole (1p-1h) and two particle-two hole (2p-2h) configurations modify the strength distributions and wavelet scales indicating the importance of the spreading width. The effect becomes more pronounced with increasing mass number. Wavelet scales remain a sensitive measure of the interplay between Landau fragmentation and the spreading width in the description of the fine structure of giant resonances.Comment: 13 pages,7 figures, regular articl

Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening?

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected

Kidney histopathology in lethal human sepsis

PURPOSE: The histopathology of sepsis-associated acute kidney injury (AKI) in critically ill patients remains an understudied area. Previous studies have identified that acute tubular necrosis (ATN) is not the only driver of sepsis-AKI. The focus of this study was to identify additional candidate processes that may drive sepsis-AKI. To do this we immunohistochemically characterized the histopathological and cellular features in various compartments of human septic kidneys. METHODS: We studied the following histopathological features: leukocyte subsets, fibroblast activation, cellular proliferation, apoptosis, and fibrin deposition in the glomerulus and the tubulointerstitium in human post-mortem kidney biopsy tissue. Biopsy tissue samples from 27 patients with sepsis-AKI were collected 33 min (range 24-150) after death in the ICU. The unaffected part of the kidneys from 12 patients undergoing total nephrectomy as a result of renal carcinoma served as controls. RESULTS: Immunohistochemical analysis revealed the presence of more neutrophils and macrophages in the glomeruli and more neutrophils in the tubulointerstitium of renal tissue from patients with sepsis compared to control renal tissue. Type II macrophages were predominant, with some macrophages expressing both type I and type II markers. In contrast, there were almost no macrophages found in control kidneys. The number of activated (myo)fibroblasts was low in the glomeruli of sepsis-AKI kidneys, yet this was not observed in the tubulointerstitium. Cell proliferation and fibrin deposition were more pronounced in the glomeruli and tubulointerstitium of sepsis-AKI than in control kidneys. CONCLUSIONS: The extensive heterogeneity of observations among and within patients emphasizes the need to thoroughly characterize patients with sepsis-AKI in a large sample of renal biopsy tissue from patients with sepsis

The renal angiopoietin/Tie2 system in lethal human sepsis

Sepsis-induced multi-organ dysfunction syndrome (MODS) still has a high mortality. Improvements await a better understanding of the pathophysiological mechanisms. The angiopoietin (Ang)1/2 and Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) ligand/receptor system is an important regulator of endothelial cell responses to severe insults. Plasma Ang2 levels are prognostic in sepsis, but data on Ang/Tie responses in organs in humans are lacking.. We hypothesized that, in kidneys of patients who died of sepsis with acute kidney injury (AKI), the Ang/Tie signaling system is changed in such a way that microvessels become destabilized

Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury

Background: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation. Methods: Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH(2)O ('low' tidal volume similar to 7.5 ml/kg; LVT) or 18 cmH(2)O ('high' tidal volume similar to 15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 mu g per animal). Non-ventilated mice served as controls. Results: HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1 beta caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression. Conclusions: Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilatio