Targeting TNFR2 as a novel therapeutic strategy for Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Accumulating experimental evidence shows the important linkage between tumor necrosis factor-α (TNF) and AD, but the exact role of TNF in AD is still not completely understood. Although TNF-inhibitors are successfully used for treating several diseases, total inhibition of TNF can cause side effects, particularly in neurological diseases. This is attributed to the opposing roles of the two TNF receptors. TNF receptor 1 (TNFR1) predominantly mediates inflammatory and pro-apoptotic signaling pathways, whereas TNF receptor 2 (TNFR2) is neuroprotective and promotes tissue regeneration. Therefore, the specific activation of TNFR2 signaling, either by directly targeting TNFR2 via TNFR2 agonists or by blocking TNFR1 signaling with TNFR1-selective antagonists, seems a promising strategy for AD therapy. This mini-review discusses the involvement of TNFR2 and its signaling pathway in AD and outlines its potential application as therapeutic target. A better understanding of the function of TNFR2 may lead to the development of a treatment for AD

Scaling up integrated primary mental health in six low- and middle-income countries: obstacles, synergies and implications for systems reform

Background There is a global drive to improve access to mental healthcare by scaling up integrated mental health into primary healthcare (PHC) systems in low- and middle-income countries (LMICs). Aims To investigate systems-level implications of efforts to scale-up integrated mental healthcare into PHC in districts in six LMICs. Method Semi-structured interviews were conducted with 121 managers and service providers. Transcribed interviews were analysed using framework analysis guided by the Consolidated Framework for Implementation Research and World Health Organization basic building blocks. Results Ensuring that interventions are synergistic with existing health system features and strengthening of the healthcare system building blocks to support integrated chronic care and task-sharing were identified as aiding integration efforts. The latter includes (a) strengthening governance to include technical support for integration efforts as well as multisectoral collaborations; (b) ring-fencing mental health budgets at district level; (c) a critical mass of mental health specialists to support task-sharing; (d) including key mental health indicators in the health information system; (e) psychotropic medication included on free essential drug lists and (f) enabling collaborative and community- oriented PHC-service delivery platforms and continuous quality improvement to aid service delivery challenges in implementation. Conclusions Scaling up integrated mental healthcare in PHC in LMICs is more complex than training general healthcare providers. Leveraging existing health system processes that are synergistic with chronic care services and strengthening healthcare system building blocks to provide a more enabling context for integration are important

Collaborative care for the detection and management of depression among adults receiving antiretroviral therapy in South Africa: study protocol for the CobALT randomised controlled trial

Background: The scale-up of antiretroviral treatment (ART) programmes has seen HIV/AIDS transition to a chronic condition characterised by high rates of comorbidity with tuberculosis, non-communicable diseases (NCDs) and mental health disorders. Depression is one such disorder that is associated with higher rates of non-adherence, progression to AIDS and greater mortality. Detection and treatment of comorbid depression is critical to achieve viral load suppression in more than 90% of those on ART and is in line with the recent 90-90-90 Joint United Nations Programme on HIV/AIDS (UNAIDS) targets. The CobALT trial aims to provide evidence on the effectiveness and cost-effectiveness of scalable interventions to reduce the treatment gap posed by the growing burden of depression among adults on lifelong ART. Methods: The study design is a pragmatic, parallel group, stratified, cluster randomised trial in 40 clinics across two rural districts of the North West Province of South Africa. The unit of randomisation is the clinic, with outcomes measured among 2000 patients on ART who screen positive for depression using the Patient Health Questionnaire (PHQ-9). Control group clinics are implementing the South African Department of Health’s Integrated Clinical Services Management model, which aims to reduce fragmentation of care in the context of rising multimorbidity, and which includes training in the Primary Care 101 (PC101) guide covering communicable diseases, NCDs, women’s health and mental disorders. In intervention clinics, we supplemented this with training specifically in the mental health components of PC101 and clinical communications skills training to support nurse-led chronic care. We strengthened the referral pathways through the introduction of a clinic-based behavioural health counsellor equipped to provide manualised depression counselling (eight sessions, individual or group), as well as adherence counselling sessions (one session, individual). The co-primary patient outcomes are a reduction in PHQ-9 scores of at least 50% from baseline and viral load suppression rates measured at 6 and 12 months, respectively. Discussion: The trial will provide real-world effectiveness of case detection and collaborative care for depression including facility-based counselling on the mental and physical outcomes for people on lifelong ART in resource-constrained settings

Effectiveness of a task-sharing collaborative care model for identification and management of depressive symptoms in patients with hypertension attending public sector primary care clinics in South Africa: pragmatic parallel cluster randomised controlled trial.

Background: We tested the real-world effectiveness of a collaborative task-sharing model on depressive symptom reduction in hypertensive Primary Health Care (PHC) patients in South Africa. Method: A pragmatic parallel cluster randomised trial in 20 clinics in the Dr Kenneth Kaunda district, North West province. PHC clinics were stratified by sub-district and randomised in a 1:1 ratio. Control clinics received care as usual (CAU), involving referral to PHC doctors and/or mental health specialists. Intervention clinics received CAU plus enhanced mental health training and a lay counselling referral service. Participant inclusion criteria were ≥ 18 years old, Patient Health Questionnaire-9 (PHQ-9) score ≥ 9 and receiving hypertension medication. Primary superiority outcome was ≥ 50% reduction in PHQ-9 score at 6 months. Statistical analyses comprised mixed effects regression models and a non-inferiority analysis. Trial registration number: NCT 02425124. Results: Between April 2015 and October 2015, 1043 participants were enrolled (504 intervention and 539 control); 82% were women; half were ≥ 55 years. At 6 and 12 months follow-up, 91% and 89% of participants were interviewed respectively. One control group participant committed suicide. There was no significant difference in the primary outcome between intervention (N=256/456) and control (N=232/492) groups (55.9% versus 50.9%; adjusted risk difference = -0.04 ([95% CI = -0.19; 0.11], p = 0.6). The difference in PHQ-9 scores was within the defined equivalence limits at 6 and 12 months for the non-inferiority analysis. Limitations: The trial was limited by low exposure to depression treatment by trial participants and by observed co-intervention in control clinics Conclusions: Incorporating lay counselling services within collaborative care models does not produce superior nor inferior outcomes to models with specialist only counselling services. Funding: This work was supported by the UK Department for International Development [201446] as well as the National Institute of Mental Health, United States of America, grant number 1R01MH100470-01. Graham Thornicroft is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) South London at King's College London and King's College Hospital NHS Foundation Trust

Scaling up integrated primary mental health in six low-and-middle income countries: obstacles, synergies and implications for systems reform

Background There is a global drive to improve access to mental healthcare by scaling up integrated mental health into primary healthcare (PHC) systems in low- and middle-income countries (LMICs). Aims To investigate systems-level implications of efforts to scale-up integrated mental healthcare into PHC in districts in six LMICs. Method Semi-structured interviews were conducted with 121 managers and service providers. Transcribed interviews were analysed using framework analysis guided by the Consolidated Framework for Implementation Research and World Health Organization basic building blocks. Results Ensuring that interventions are synergistic with existing health system features and strengthening of the healthcare system building blocks to support integrated chronic care and task-sharing were identified as aiding integration efforts. The latter includes (a) strengthening governance to include technical support for integration efforts as well as multisectoral collaborations; (b) ring-fencing mental health budgets at district level; (c) a critical mass of mental health specialists to support task-sharing; (d) including key mental health indicators in the health information system; (e) psychotropic medication included on free essential drug lists and (f) enabling collaborative and community- oriented PHC-service delivery platforms and continuous quality improvement to aid service delivery challenges in implementation. Conclusions Scaling up integrated mental healthcare in PHC in LMICs is more complex than training general healthcare providers. Leveraging existing health system processes that are synergistic with chronic care services and strengthening healthcare system building blocks to provide a more enabling context for integration are important

Collaborative care for the detection and management of depression among adults with hypertension in South Africa: study protocol for the PRIME-SA randomised controlled trial

Background: The high co-morbidity of mental disorders, particularly depression, with non-communicable diseases (NCDs) such as cardiovascular disease (CVD), is concerning given the rising burden of NCDs globally, and the role depression plays in confounding prevention and treatment of NCDs. The objective of this randomised control trial (RCT) is to determine the real-world effectiveness of strengthened depression identification and management on depression outcomes in hypertensive patients attending primary health care (PHC) facilities in South Africa (SA). Methods/design: The study design is a pragmatic, two-arm, parallel-cluster RCT, the unit of randomisation being the clinics, with outcomes being measured for individual participants. The 20 largest eligible clinics from one district in the North West Province are enrolled in the trial. Equal numbers of hypertensive patients (n = 50) identified as having depression using the Patient Health Questionnaire (PHQ-9) are enrolled from each clinic, making up a total of 1000 participants with 500 in each arm. The nurse clinicians in the control facilities receive the standard training in Primary Care 101 (PC101), a clinical decision support tool for integrated chronic care that includes guidelines for hypertension and depression care. Referral pathways available include referrals to PHC physicians, clinical or counselling psychologists and outpatient psychiatric and psychological services. In the intervention clinics, this training is supplemented with strengthened training in the depression components of PC101 as well as training in clinical communication skills for nurse-led chronic care. Referral pathways are strengthened through the introduction of a facility-based behavioural health counsellor, trained to provide structured manualised counselling for depression and adherence counselling for all chronic conditions. The primary outcome is defined as at least 50% reduction in PHQ-9 score measured at 6 months. Discussion: This trial should provide evidence of the real world effectiveness of strengtheneddepression identification and collaborative management on health outcomes of hypertensive patients withcomorbid depression attending PHC facilities in South Africa

HeAlth System StrEngThening in four sub-Saharan African countries (ASSET) to achieve high-quality, evidence-informed surgical, maternal and newborn, and primary care: protocol for pre-implementation phase studies

To achieve universal health coverage, health system strengthening (HSS) is required to support the of delivery of high-quality care. The aim of the National Institute for Health Research Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme, with three healthcare platforms involving eight work-packages. Key to effective health system strengthening (HSS) is the pre-implementation phase of research where efforts focus on applying participatory methods to embed the research programme within the existing health system. To conceptualise the approach, we provide an overview of the key methods applied across work-package to address this important phase of research conducted between 2017 and 2021. Work-packages are being undertaken in publicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe. Stakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers are the main research participants. In each work-package, initial activities engage stakeholders and build relationships to ensure co-production and ownership of HSSIs. A mixed-methods approach is then applied to understand and address determinants of high-quality care delivery. Methods such as situation analysis, cross-sectional surveys, interviews and focus group discussions are adopted to each work-package aim and context. At the end of the pre-implementation phase, findings are disseminated using focus group discussions and participatory Theory of Change workshops where stakeholders from each work package use findings to select HSSIs and develop a programme theory. ASSET places a strong emphasis of the pre-implementation phase in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and stakeholder engagement. This common approach will inform the design and evaluation of the HSSIs to increase effectiveness across work packages and contexts, to better understand what works, for whom, and how

Development and evaluation of improved gene therapy strategies for hemophilia, based on adeno-associated viral vectors

Hemofilie is een erfelijke bloedstollingsziekte die veroorzaakt wordt do or een gebrek aan functionele bloedstollingsfactoren VIII (FVIII) of IX (FIX). Patiënten met hemofilie lijden aan herhaaldelijke bloedingen in z achte weefsels, gewrichten en spieren, welke vaak aanleiding geven tot i nvaliderende gewrichtsaandoeningen. De ziekte is X-gebonden en treft naa r schatting 400,000 mensen wereldwijd. De huidige behandeling bestaat ui t de injectie van stollingsfactorconcentraten in respons op bloedingen o f ook profylactisch. Nochtans is deze eiwit-substitutietherapie beperkt door de gelimiteerde beschikbaarheid, hoge kostprijs en het risico om in hibitoren te ontwikkelen die de verdere therapie kunnen ondermijnen. De introductie van een functionele kopij van het FVIII of FIX gen in de cel len van de patiënt, via gentherapie, zou een interessant alternatief kun nen bieden voor de behandeling van hemofilie en zelfs tot genezing kunne n leiden. Doch, de voornaamste vereiste is de ontwikkeling van een effic iënt en veilig gentransfersysteem. Een van de meest veelbelovende vector en werd afgeleid van het adeno-geassocieerde virus (AAV), hoewel klinisc he studies uitwijzen dat er een sterke noodzaak is om hun therapeutische index te verbeteren. Daarom is het onze doelstelling van verbeterde gen therapie-strategieën voor hemofilie te ontwikkelen, gebaseerd op deze AA V vectoren, en deze te evalueren in preklinische diermodellen. Vooreerst stelden we de hypothese dat de modificatie van de moleculaire interactie tussen de AAV vector en het doelweefsel (lever), via serotype -switching, de transductie efficiëntie en transgene FIX expressie zou ku nnen verbeteren. Daartoe werd een vergelijkende studie uitgevoerd tussen alternatieve AAV8 en AAV9 serotypes. Na intraveneuze injectie resulteer den beide AAV8-FIX en AAV9-FIX vectoren in supra-fysiologische FIX expre ssie, die leidde tot de stabiele correctie van de bloedstollingsziekte i n hemofilie B muizen. Deze resultaten konden toegeschreven worden aan de efficiënte hepatische gentransfer door beide serotypes. Bovendien leidd en de AAV9 vectoren tot een onverwachte, wijd verspreide transductie van het muis-myocardium op een dosis-afhankelijke wijze. Het AAV9 cardiotro pisme was redelijk opmerkelijk en ongezien vermits het hart gekend stond als moeilijk te transduceren met de meeste virale vectoren. Daarom zoud en AAV9 vectoren ook veelbelovend kunnen zijn voor de behandeling van ge netische en verworven hartziekten. Vervolgens werd de hypothese gesteld dat de modificatie van het AAV vect or genoom, door het rationeel design van de FIX expressiecassette, de al gehele prestatie van de vector zou kunnen verbeteren. Ten eerste, ontwik kelden we een nieuwe methode, gebaseerd op in silico analyse, om krachti ge en leverspecifieke promotoren/enhancers de novo te ontwerpen. Via een differentiële screening van microarray expressiedata en een computation ele benadering, die gebruik maakt van een nieuw data-mining algoritme (D DM methode), werden verschillende leverspecifieke promotoren (LSPs) en h epatocyt-specifieke enhancers (HSEs) geïdentificeerd. Deze nieuwe regula torische elementen konden in vivo gevalideerd worden via hydrodynamische screening en AAV9 transductie in muizen. In het bijzonder konden 70% va n de geselecteerde HSEs de FIX expressie verder verhogen vanaf de kracht ige transthyretin (TTR) minimale LSP, waarbij HSE8 geïdentificeerd werd als de sterkste HSE. Opmerkelijk is dat de HSE8-TTRmin promotor therapeu tische FIX niveaus bereikte, die leidden tot de stabiele correctie van d e bloedstollingsziekte in hemofilie B muizen zelfs bij lage vectordosiss en. Verder kon de werkelijke leverspecificiteit van deze nieuwe regulato rische elementen bevestigd worden, zelfs bij zeer hoge vectordosissen. D eze resultaten valideren duidelijk de DDM methode voor het identificeren van robuuste, leverspecifieke regulatorische elementen de novo. Ten tweede, verkregen we een krachtig, leverspecifiek controle-element v ia een in vitro selectie methode die eerder beschreven werd. Na AAV9 gen transfer bereikte deze synthetische hepatocyt-specifieke enhancer (Synth Enh), gekoppeld aan de TTR promotor, stabiele supra-fysiologische FIX ex pressie vergelijkbaar met die behaald door de robuuste HSE8-TTRmin promo tor bij dezelfde vectordosis. Deze resultaten valideren beide de in vitr o enhancer selectie en de DDM methode als aantrekkelijke, complementaire methoden om krachtige, leverspecifieke expressiecassettes te genereren. Tenslotte toonden we aan dat de optimalisatie van het codongebruik en cis-agerende elementen (in het bijzonder introns) in dit TTR/SynthEnh c onstruct de transgene FIX expressie verder kon verbeteren. In conclusie toont de huidige studie aan dat het gebruik van alternatiev e AAV serotypes in combinatie met de optimalisatie van het AAV vector de sign, robuuste leverspecifieke vectoren kan opleveren. Dit is van bijzon der belang aangezien de ontwikkeling van krachtige AAV vectoren zou kunn en leiden tot therapeutische expressieniveaus bij lagere en dus veiliger e vectordosissen. Daarenboven zou de verhindering van off-target trans gene expressie de algehele veiligheid van de vectoren kunnen verbeteren. Deze bemoedigende resultaten dragen bij tot de ontwikkeling van genther apie-vectoren met een verbeterde therapeutische index en kunnen uiteinde lijk het pad effenen in de richting van gentherapie voor hemofilie.status: publishe

Gene Therapy for Von Willebrand Disease

An acquired bleeding disorder with clinical and laboratory features similar to inherited von Willebrand disease (VWD) has been reported since 1968 and has been considered to be very rare. It was defined as acquired von Willebrand syndrome (aVWS) because it is similar to VWD and occurs late in life in patients with a negative history of bleeding who suffer mainly from lymphoproliferative, cardiovascular, and myeloproliferative disorders. In most instances aVWS is identified because of bleeding complications, and more than 80% of the patients are active bleeders. New bleeds after the diagnosis has been established occur in about 20% of patients, 33% of whom can require surgery within 1 year of diagnosis. Owing to the high risk of new bleeds and the necessity for surgery in many patients, it is important to establish a firm diagnosis and implement appropriate treatment in these patients. © 2011 Blackwell Publishing Ltd.SCOPUS: ch.binfo:eu-repo/semantics/publishe