Clinical outcomes of treatment with idebenone in Leber's hereditary optic neuropathy in the Netherlands:A national cohort study

Purpose The purpose of the study was to present results from a national Dutch cohort of patients with Leber's Hereditary Optic Neuropathy (LHON) treated with idebenone. Methods The multicentre, open-label, retrospective evaluation of the long-term outcome of idebenone treatment of Dutch LHON patients on visual function and on thickness of the retinal ganglion cell layer. Patients included in the analysis had a confirmed mutation in their mitochondrial DNA encoding either of the seven subunits of complex I, had a reported loss of vision in at least one eye and had a follow-up of more than 6 months after their treatment was started. Control visits involved routine clinical examinations of visual function and retinal structure at (1) the start of treatment, (2) nadir (time of lowest visual acuity), (3) the time of recovery (if any), (4) the time of termination of treatment and (5) more than 6 months after termination of the treatment. Results Data from 72 patients were analysed. Treatment duration was 23.8 +/- 14.4 (mean +/- SD) months. A positive response, that is either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS), occurred in 53% and 11% of the patients, respectively. The magnitude of CRR was 0.41 +/- 1.54 logMAR. CRR of visual acuity is associated with recovery of colour discrimination. The thickness of both the ganglion cell complex (GCC) and the retinal nerve fibre layer (RNFL) is irreversibly reduced. Conclusion Our results confirm that idebenone may help to restore or maintain visual function. Whether this effect will persist is still unknown. Thinning of retinal neural tissue appears to be permanent

C4b-Binding Protein Is Present in Affected Areas of Myocardial Infarction during the Acute Inflammatory Phase and Covers a Larger Area than C3

BACKGROUND: During myocardial infarction reduced blood flow in the heart muscle results in cell death. These dying/dead cells have been reported to bind several plasma proteins such as IgM and C-reactive protein (CRP). In the present study we investigated whether fluid-phase complement inhibitor C4b-binding protein (C4BP) would also bind to the infarcted heart tissue. METHODS AND FINDINGS: Initial studies using immunohistochemistry on tissue arrays for several cardiovascular disorders indicated that C4BP can be found in heart tissue in several cardiac diseases but that it is most abundantly found in acute myocardial infarction (AMI). This condition was studied in more detail by analyzing the time window and extent of C4BP positivity. The binding of C4BP correlates to the same locations as C3b, a marker known to correlate to the patterns of IgM and CRP staining. Based on criteria that describe the time after infarction we were able to pinpoint that C4BP binding is a relatively early marker of tissue damage in myocardial infarction with a peak of binding between 12 hours and 5 days subsequent to AMI, the phase in which infiltration of neutrophilic granulocytes in the heart is the most extensive. CONCLUSIONS: C4BP, an important fluid-phase inhibitor of the classical and lectin pathway of complement activation binds to jeopardized cardiomyocytes early after AMI and co-localizes to other well known markers such as C3b

Intention and action in retirement preparation

Many people delay their preparation for retirement. Policy-makers often attempt to motivate people to take timely action by increasing the perceived importance of retirement saving, yet the effectiveness of such strategies can be doubted. We examined why a strategy of emphasizing importance may be ineffective by distinguishing between intention to prepare for retirement and action in actually taking steps toward preparation. Two surveys (n1 = 1171; n2 = 832) showed that importance and difficulty were both predictive of people's intentions to prepare for retirement, but that difficulty was a much stronger predictor of people's actual actions. Using data from an additional survey (n3 = 986), a series of follow-up tests provided further evidence that difficulty of retirement preparation is a stronger predictor of inaction than importance of retirement saving. These findings help explain why policies aimed at simplifying retirement preparation (e.g., automatic enrollment) have been more successful than policies aimed at increasing the importance of retirement saving (e.g., tax advantages)

C4b-Binding Protein Deposition is Induced in Diseased Aortic Heart Valves, Coinciding with C3d

Background and aim of the study: It has been found recently that activated complement is more widespread in diseased aortic valves compared to the endogenous complement inhibitors C1-inhibitor and clusterin. Previously, another endogenous inhibitor of complement, C4b-binding protein (C4BP) has been described in atherosclerotic diseased coronary arteries. The study aim was to analyze C4BP levels in diseased aortic valves. Methods: Aortic valve tissue was derived from surgical procedures and classified as 'degenerative', 'atherosclerotic' or 'atherosclerotic with bacterial infection'. Valves were stained with specific antibodies against C4BP, C3d and caspase-3. Areas of positivity were then quantified using computer assisted morphometry. Results: In atherosclerotic valves, the areas of C4BP and C3d positivity (38.8 +/- 0.4% versus 32.7 +/- 1.0%, respectively) were significantly higher compared to the degenerative and control groups. In atherosclerotic valves with bacterial infection, the area of positivity for C4BP was even further increased compared to atherosclerotic valves (65.1 +/- 1.2%; 70.1 +/- 1.9% for C3d). The areas of C4BP and C3d positivity were not significantly different in all groups. Caspase-3 was only present in <10% of endothelial cells in the atherosclerotic valves without bacterial infection and in neutrophilic granulocytes in atherosclerotic valves, with and without bacterial infection. Conclusion: It has been shown for the first time that C4BP is deposited in the diseased aortic valve, coinciding with C3d. The area of C4BP positivity was more extensive compared to the areas of other endogenous complement inhibitors (C1-inhibitor and clusterin)

Psychological interventions to prevent relapse in anxiety and depression: A systematic review and meta-analysis

Abstract Objectives The aim of this review is to establish the effectiveness of psychological relapse prevention interventions, as stand-alone interventions and in combination with maintenance antide pressant treatment (M-ADM) or antidepressant medication (ADM) discontinuation for patients with remitted anxiety disorders or major depressive disorders (MDD). Methods A systematic review and a meta-analysis were conducted. A literature search was con ducted in PubMed, PsycINFO and Embase for randomised controlled trials (RCTs) compar ing psychological relapse prevention interventions to treatment as usual (TAU), with the proportion of relapse/recurrence and/or time to relapse/recurrence as outcome measure. Results Thirty-six RCTs were included. During a 24-month period, psychological interventions signif icantly reduced risk of relapse/recurrence for patients with remitted MDD (RR 0.76, 95% CI: 0.68–0.86, p<0.001). This effect persisted with longer follow-up periods, although these results were less robust. Also, psychological interventions combined with M-ADM signifi cantly reduced relapse during a 24-month period (RR 0.76, 95% CI: 0.62–0.94, p = 0.010), but this effect was not significant for longer follow-up periods. No meta-analysis could be performed on relapse prevention in anxiety disorders, as only two studies focused on relapse prevention in anxiety disorders. Conclusions In patients with remitted MDD, psychological relapse prevention interventions substantially reduce risk of relapse/recurrence. It is recommended to offer these interventions to remitted MDD patients. Studies on anxiety disorders are needed

Evaluation of a Blended Relapse Prevention Program for Anxiety and Depression in General Practice: Qualitative Study

Background: Existing studies have yet to investigate the perspectives of patients and professionals concerning relapse prevention programs for patients with remitted anxiety or depressive disorders in primary care. User opinions should be considered when optimizing the use and implementation of interventions. Objective: This study aimed to evaluate the GET READY relapse prevention programs for patients with remitted anxiety or depressive disorders in general practice. Methods: Semistructured interviews (N=26) and focus group interviews (N=2) with patients and mental health professionals (MHPs) in the Netherlands were performed. Patients with remitted anxiety or depressive disorders and their MHPs who participated in the GET READY study were interviewed individually. Findings from the interviews were tested in focus group interviews with patients and MHPs. Data were analyzed using thematic analysis. Results: Participants were positive about the program because it created awareness of relapse risks. Lack of motivation, lack of recognizability, lack of support from the MHP, and symptom severity (too low or too high) appeared to be limiting factors in the use of the program. MHPs play a crucial role in motivating and supporting patients in relapse prevention. The perspectives of patients and MHPs were largely in accordance, although they had different perspectives concerning responsibilities for taking initiative. Conclusions: The implementation of the GET READY program was challenging. Guidance from MHPs should be offered for relapse prevention programs based on eHealth. Both MHPs and patients should align their expectations concerning responsibilities in advance to ensure optimal usage. Usage of blended relapse prevention programs may be further enhanced by diagnosis-specific programs and easily accessible support from MHPs

Evaluatie van een blended terugvalpreventie programma voor angst en depressie in de huisartsenpraktijk: kwalitatieve studie

Samenvatting Doel: Het evalueren van het GET READY-terugvalpreventieprogramma voor patiënten met herstelde angst- of depressieve stoornissen in de huisartsenpraktijk. Methode: Er werden semigestructureerde interviews (n = 26) en focusgroepinterviews (n = 2) gehouden met patiënten en praktijkondersteuners huisarts GGZ (POH-GGZ). Patiënten met herstelde angst- of depressieve stoornissen en hun POH-GGZ die deelnamen aan de GET READY-studie werden individueel geïnterviewd. Bevindingen uit de interviews werden getoetst in focusgroepinterviews met patiënten en POH-GGZ. Data werden geanalyseerd door het toepassen van thematische analyse. Resultaat: Patiënten waren positief over het programma omdat het bewustwording creëerde over terugvalrisico’s. Een gebrek aan motivatie, herkenbaarheid en steun van de POH-GGZ, samen met ernst van symptomen waren belemmerend in het gebruik van het programma. POH-GGZ spelen een onmisbare rol in het motiveren en steunen van patiënten bij terugvalpreventie. Opvattingen van patiënten en POH-GGZ kwamen grotendeels overeen, wel hadden zij andere opvattingen over de verantwoordelijkheid qua initiatief nemen. Discussie: De implementatie van het GET READY programma was uitdagend. Begeleiding door de POH-GGZ moet bij terugvalpreventieprogramma’s worden aangeboden op basis van eHealth. Conclusie: Begeleiding door de POH-GGZ moet bij terugvalpreventieprogramma’s, die gebaseerd zijn op eHealth, worden aangeboden

The GET READY relapse prevention programme for anxiety and depression: a mixed-methods study protocol

Abstract Background Since anxiety and depressive disorders often recur, self-management competencies are crucial for improving the long-term course of anxiety and depressive disorders. However, few relapse prevention programmes are available that focus on improving self-management. E-health combined with personal contact with a mental health professional in general practice might be a promising approach for relapse prevention. In this protocol, the GET READY (Guided E-healTh for RElapse prevention in Anxiety and Depression) study will be described in which a relapse prevention programme is developed, implemented and evaluated. The aim of the study is to determine patients’ usage of the programme and the associated course of their symptoms, to examine barriers and facilitators of implementation, and to assess patients’ satisfaction with the programme. Methods Participants are discharged from mental healthcare services, and are in complete or partial remission. They receive access to an E-health platform, combined with regular contact with a mental health professional in general practices. Online questionnaires will be completed at baseline and after 3, 6 and 9 months. Also, semi-structured qualitative individual interviews and focus group interviews will be conducted with patients and mental health professionals. Discussion This mixed-methods observational cohort study will provide insights into the use of a relapse prevention programme in relation to the occurrence of symptoms, as well as in its implementation and evaluation. Using the results of this study, the relapse prevention programme can be adapted in accordance with the needs of patients and mental health professionals. If this programme is shown to be acceptable, a randomized controlled trial may be conducted to test its efficacy. Trial registration Retrospectively registered in the Netherlands Trial Register (NTR7574; 25 October 2018)

Usage Intensity of a Relapse Prevention Program and Its Relation to Symptom Severity in Remitted Patients With Anxiety and Depression: Pre-Post Study

Background: Given that relapse is common in patients in remission from anxiety and depressive disorders, relapse prevention is needed in the maintenance phase. Although existing psychological relapse prevention interventions have proven to be effective, they are not explicitly based on patients’ preferences. Hence, we developed a blended relapse prevention program based on patients’ preferences, which was delivered in primary care practices by mental health professionals (MHPs). This program comprises contact with MHPs, completion of core and optional online modules (including a relapse prevention plan), and keeping a mood and anxiety diary in which patients can monitor their symptoms. Objective: The aims of this study were to provide insight into (1) usage intensity of the program (over time), (2) the course of symptoms during the 9 months of the study, and (3) the association between usage intensity and the course of symptoms. Methods: The Guided E-healTh for RElapse prevention in Anxiety and Depression (GET READY) program was guided by 54 MHPs working in primary care practices. Patients in remission from anxiety and depressive disorders were included. Demographic and clinical characteristics, including anxiety and depressive symptoms, were collected via questionnaires at baseline and after 3, 6, and 9 months. Log data were collected to assess the usage intensity of the program. Results: A total of 113 patients participated in the study. Twenty-seven patients (23.9%) met the criteria for the minimal usage intensity measure. The core modules were used by ≥70% of the patients, while the optional modules were used by <40% of the patients. Usage decreased quickly over time. Anxiety and depressive symptoms remained stable across the total sample; a minority of 15% (12/79) of patients experienced a relapse in their anxiety symptoms, while 10% (8/79) experienced a relapse in their depressive symptoms. Generalized estimating equations analysis indicated a significant association between more frequent face-to-face contact with the MHPs and an increase in both anxiety symptoms (β=.84, 95% CI .39-1.29) and depressive symptoms (β=1.12, 95% CI 0.45-1.79). Diary entries and the number of completed modules were not significantly associated with the course of symptoms

Arterial Blood Pressure Induces Transient C4b-Binding Protein in Human Saphenous Vein Grafts

Background: Complement is an important mediator in arterial blood pressure-induced vein graft failure. Previously, we noted activation of cell protective mechanisms in human saphenous veins too. Here we have analyzed whether C4b-binding protein (C4bp), an endogenous complement inhibitor, is present in the vein wall. Methods: Human saphenous vein segments obtained from patients undergoing coronary artery bypass grafting (n = 55) were perfused in vitro at arterial blood pressure with either autologous blood for 1, 2, 4, or 6 hr or with autologous blood supplemented with reactive oxygen species scavenger N-acetylcysteine. The segments were subsequently analyzed quantitatively for presence of C4bp and complement activation product C3d using immunohistochemistry. Results: Perfusion induced deposition of C3d and C4bp within the media of the vessel wall, which increased reproducibly and significantly over a period of 4 hr up to 3.8% for C3d and 81% for C4bp of the total vessel area. Remarkably after 6 hr of perfusion, the C3d-positive area decreased significantly to 1.3% and the C4bp-positive area to 19% of the total area of the vein. The areas positive for both C4bp and C3d were increased in the presence of N-acetylcysteine. Conclusions: Exposure to arterial blood pressure leads to a transient presence of C4bp in the vein wall. This may be part of a cell-protective mechanism to counteract arterial blood pressure-induced cellular stress and inflammation in grafted veins