Pulmonary hypertension and homebased (PHAHB) exercise intervention: protocol for a feasibility study

Introduction Novel therapies for pulmonary hypertension (PH) have improved survival and slowed disease progression. However, patients still present with symptoms of exertional dyspnoea and fatigue, which impacts their ability to perform activities of daily living, reduces exercise tolerance and impairs their quality of life (QoL). Exercise training has shown to be safe and effective at enhancing QoL and physical function in PH patients, yet it remains an underused adjunct therapy. Most exercise training for PH patients has been offered through hospital-based programmes. Home-based exercise programmes provide an alternative model that has the potential to increase the availability and accessibility of exercise training as an adjunct therapy in PH. The purpose of this study is to investigate the feasibility, acceptability, utility and safety of a novel remotely supervised home-based PH exercise programme. Methods Single arm intervention with a pre/post comparisons design and a follow-up maintenance phase will be employed. Eligible participants (n=25) will be recruited from the Mater Misericordiae University Hospital PH Unit. Participants will undergo a 10-week home-based exercise programme, with induction training, support materials, telecommunication support and health coaching sessions followed by a 10-week maintenance phase. The primary outcomes are feasibility, acceptability, utility and safety of the intervention. Secondary outcomes will include the impact of the intervention on exercise capacity, physical activity, strength, health-related QoL and exercise self-efficacy. Ethics and dissemination Ethics approval has been obtained from the Mater Misericordiae Institutional Review Board REF:1/378/2032 and Dublin City University Research Ethics DCUREC/2018/246. A manuscript of the results will be submitted to a peer-reviewed journal and results will be presented at conferences, community and consumer forums and hospital research conferences. Trial registration number ISRCTN83783446; Pre-result

Exploration of physical activity knowledge, preferences and support needs among pulmonary hypertension patients

Objective: Physical activity (PA) is an established adjunct therapy for pulmonary hypertension (PH) patients to mitigate PH symptoms and improve quality of life. However, PA engagement within this population remains low. This study investigated PH patients’ knowledge of PA, recalled advice, exercise preferences and PA support needs. Methods: Semi-structured interviews were conducted with 19 adults (mean age 50 years; SD ±12 years) diagnosed with PH, living in Ireland. Interview scripts were digitally recorded and transcribed verbatim. Thematic analysis was used to analyse the data. Results: Four key themes were identified: Lack of PA knowledge; exercise setting preference; accountability and monitoring; and clinician delivered PA information and guidance. Conclusion: This study found that PH clinicians provide suboptimal PA advice, yet patients desired clinician-delivered PA guidance. Home-based exercise was preferred with monitoring and external accountability deemed as important to facilitate sustained engagement. Practice implications: PH clinicians are well positioned to play a critical role in assisting and empowering PH patients to engage in PA. Providing training and education to PH clinicians regarding exercise prescription may be beneficial. Further research is needed to evaluate the feasibility and efficacy of home-based exercise interventions to improve quality of life and physical activity in PH

Safety, Feasibility and Effectiveness of the remotely delivered Pulmonary Hypertension And Home-Based (PHAHB) Physical Activity intervention

Background Pulmonary hypertension (PH) is a heterogeneous condition, associated with a high symptom burden and a substantial loss of exercise capacity. Despite prior safety concerns regarding physical exertion, exercise training as a supportive therapy is now recommended for PH patients. Currently, most programs are hospital-based, which limits accessibility. There is a need to provide alternative approaches for physical activity engagement for PH patients. The aim of this research was to develop, implement and evaluate the safety, feasibility, and effectiveness of home-based physical activity intervention for PH. Methods An entirely remotely delivered home-based exercise intervention underpinned by behaviour change theory and informed by end-users, was assessed using a single-arm feasibility study design. Participants (n=19; 80% female) with a mean (±sd) age of 49.9±15.9 y with a diagnosis of PH undertook a 10-week, home-based exercise intervention with induction training, support materials, telecommunication support, health coaching, exercise training, and assessments, all remotely delivered. Training involved respiratory training along with a combination of aerobic and resistance exercises. Results The intervention was deemed safe as no adverse events were reported. A high level of feasibility was demonstrated as the protocol was implemented as intended, sustained a high level of engagement and adherence and was well accepted by participants in terms of enjoyment and utility. There was a significant improvement in functional capacity, physical activity, exercise self-efficacy and quality of life (QoL), between baseline and post-training. Conclusion The study demonstrates that an entirely remotely delivered home-based exercise program is safe, feasible and effective in improving functional capacity, physical activity, and QoL in PH patients

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

Payers' views of the changes arising through the possible adoption of adaptive pathways

Payers are a major stakeholder in any considerations and initiatives concerning adaptive licensing of new medicinal products, also referred to as Medicines Adaptive Pathways to patients (MAPPs). Firstly, the scope and necessity of MAPPs need further scrutiny, especially with regard to the definition of unmet need. Conditional approval pathways already exist for new medicines for seriously debilitating or life-threatening diseases and only a limited number of new medicines are innovative. Secondly, MAPPs will result in new medicines on the market with limited evidence about their effectiveness and safety. Additional data are to be collected after approval. Consequently, adaptive pathways may increase the risk of exposing patients to ineffective or unsafe medicines. We have already seen medicines approved conventionally that subsequently proved ineffective or unsafe amongst a wider, more co-morbid population as well as medicines that could have been considered for approval under MAPPs but subsequently proved ineffective or unsafe in Phase III trials and were never licensed. Thirdly, MAPPs also put high demands on payers. Routine collection of patient level data is difficult with high transaction costs. It is not clear who will fund these. Other challenges for payers include shifts in the risk governance framework, implications for evaluation and HTA, increased complexity of setting prices, difficulty with ensuring equity in the allocation of resources, definition of responsibility and liability and implementation of stratified use. Exit strategies also need to be agreed in advance, including price reductions, rebates, or reimbursement withdrawals when price premiums are not justified. These issues and concerns will be discussed in detail including potential ways forward

Evaluating the Current Status of American Shad Stocks in Three Virginia Rivers

Directed commercial fisheries for American shad Alosa sapidissima in the primary Virginia tributaries of the Chesapeake Bay have been under moratorium since 1994. Monitoring of adult American shad within these rivers has been ongoing since 1998 through a cooperative program involving commercial fishers. The monitoring program is designed to mimic traditional commercial fishing practices so that stock status can be inferred by comparing contemporary catch-per-unit-effort levels with those derived from historic logbooks. In this paper, we present analyses of the available monitoring and historic catch rate data along with updated stock status information for American shad in the James, York, and Rappahannock rivers. Two analytical methods were used to derive annual indices of relative abundance; both methods yielded very similar patterns for each river system. Comparisons of contemporary and historic indices of relative abundance suggest that American shad in the James and York rivers continue to persist at low levels of abundance. Measures of stock abundance in the Rappahannock River have been higher than the logbook reference value for much of the monitoring period. However, current moratoria and restoration strategies, which include hatchery releases of fry, the removal of obstructions blocking spawning and nursery habitat, and reductions in bycatch from other fisheries, should continue into the foreseeable future

Policies for biosimilar uptake in Europe : an overview

Background: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. Objectives: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. Methods: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. Results: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. Conclusions: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market

Elevated plasma CXCL12 alpha is associated with a poorer prognosis in pulmonary arterial hypertension.

Recent work in preclinical models suggests that signalling via the pro-angiogenic and proinflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortalit

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups