A Strep A vaccine global demand and return on investment forecast to inform industry research and development prioritization.

Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep A diseases globally. This study presents a novel Strep A vaccine global demand and financial forecast model with estimates of potential global demand and associated revenue and profits for a hypothetical Strep A vaccine as well as a net present value (NPV) analysis of return on capital investments required to develop the vaccine. A positive NPV was calculated for a variety of developer scenarios and target populations, including the global rollout of the vaccine in private and public markets by a multinational pharmaceutical corporation and a staged rollout by a developing country vaccine manufacturer for both infant and child populations. The results suggest there is a viable commercial market for a Strep A vaccine. It is hoped that this study will help to inform industry decision-making and drive increased prioritization of, and investment in, Strep A vaccine research and development.

Tackling healthcare access barriers for individuals with autism from diagnosis to adulthood.

Most individuals with autism spectrum disorder (ASD)-a complex, life-long developmental disorder-do not have access to the care required to address their diverse health needs. Here, we review: (1) common barriers to healthcare access (shortage/cost of services; physician awareness; stigma); (2) barriers encountered primarily during childhood (limited screening/diagnosis; unclear referral pathways), transition to adulthood (insufficient healthcare transition services; suboptimal physician awareness of healthcare needs) and adulthood (shortage of services/limited insurance; communication difficulties with physicians; limited awareness of healthcare needs of aging adults); and (3) advances in research/program development for better healthcare access. A robust understanding of barriers to accessing healthcare across the lifespan of autistic individuals is critical to ensuring the best use of healthcare resources to improve social, physical, and mental health outcomes. Stakeholders must strengthen healthcare service provision by coming together to: better understand healthcare needs of underserved populations; strengthen medical training on care of autistic individuals; increase public awareness of ASD; promote research into/uptake of tools for ASD screening, diagnosis, and treatment; understand specific healthcare needs of autistic individuals in lower resource countries; and conduct longitudinal studies to understand the lifetime health, social, and economic impacts of ASD and enable the evaluation of novel approaches to increasing healthcare access. IMPACT: Despite the growing body of evidence, our understanding of barriers to healthcare encountered by individuals with ASD remains limited, particularly beyond childhood and in lower resource countries. We describe current and emerging barriers to healthcare access encountered by individuals with ASD across the lifespan. We recommend that stakeholders develop evidence-informed policies, programs, and technologies that address barriers to healthcare access for individuals with ASD and consider broad, equitable implementation to maximize impact.

Inclusion, diversity, equity, and accessibility: From organizational responsibility to leadership competency.

An awakening to systemic anti-Black racism, anti-Indigenous racism, and harmful colonial structures in the context of a pandemic has made health inequities and injustices impossible to ignore, and is driving healthcare organizations to establish and strengthen approaches to inclusion, diversity, equity, and accessibility (IDEA). Health research and care organizations, which are shaping the future of healthcare, have a responsibility to make IDEA central to their missions. Many organizations are taking concrete action critically important to embedding IDEA principles, but durable change will not be achieved until IDEA becomes a core leadership competency. Drawing from the literature and consultation with individuals recognized for excellence in IDEA-informed leadership, this study will help Canadian healthcare and health research leaders-particularly those without lived experience-understand what it means to embed IDEA within traditional leadership competencies and propose opportunities to achieve durable change by rethinking governance, mentorship, and performance management through an IDEA lens.

Fostering Clinical Research in the Community Hospital: Opportunities and Best Practices.

With potential to improve patient outcomes, quality of care and cost-effectiveness, clinical research activity in community hospitals has recently begun to increase. Recognizing that establishing or strengthening a clinical research program in this setting is an important, complex and challenging undertaking, this article introduces many of the resources, best practices and success stories that community hospitals can draw upon to develop and incentivize clinical researchers, operationalize the clinical research enterprise and make clinical research impactful.

Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer's Disease and Related Dementias and Strategic Implications for Stakeholders.

While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

From the voices of people with haemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies.

INTRODUCTION: Haemophilia A is a chronic disease requiring frequent intravenous infusions of recombinant factor VIII. Previous studies have shown that challenges associated with current treatments may have significant impacts on quality of life (QoL) that are as important as the health outcomes conferred by the therapy. Emerging therapeutic innovations offer the potential to mitigate treatment-related challenges, and it is therefore important to develop a better understanding of patient and caregiver experiences with existing haemophilia A treatments in order to characterize the full value of new treatments. AIM: To gather firsthand perspectives from people with haemophilia A (PWHA) and caregivers on the challenges with current treatment, their impact on QoL and desired improvements in future therapies. METHODS: Qualitative insights were gathered from 20 non-inhibitor PWHA or caregivers of PWHA across Canada through one-on-one interviews; insights were further explored through focus group sessions to uncover overarching themes and prioritize issues with current treatments. RESULTS: PWHA and caregivers identified several challenges, including administration of intravenous infusions, coordination of treatment schedules and ensuring adequate medication and supplies. Participants described how these challenges impact psychosocial well-being, physical health, personal/social life and work. Alternate modes of administration and longer-lasting treatment effects were identified as desired improvements over current treatments. CONCLUSION: This study emphasizes the impact that existing haemophilia A treatments have on psychological well-being, employment opportunities and adherence to treatment regimens. These considerations may help to inform decision-making for policymakers and health systems around the true value of new therapies entering the haemophilia market.

Organisational best practices towards gender equality in science and medicine.

In August 2018, the president of the World Bank noted that "'Human capital'-the potential of individuals-is going to be the most important long-term investment any country can make for its people's future prosperity and quality of life". Nevertheless, leaders and practitioners in academic science and medicine continue to be unaware of and poorly educated about the nature, extent, and impact of barriers to full participation of women and minorities in science and medicine around the world. This lack of awareness and education results in failures to fully mobilise the human capital of half the population and limits global technological and medical advancements. The chronic lack of recruitment, promotion, and retention of women in science and medicine is due to systemic, structural, organisational, institutional, cultural, and societal barriers to equity and inclusion. These barriers must be identified and removed through increased awareness of the challenges combined with evidence-based, data-driven approaches leading to measurable targets and outcomes. In this Review, we discuss these issues and highlight actions that could achieve gender equality in science and medicine. We survey approaches and insights that have helped to identify and remove systemic bias and barriers in science and medicine, and propose tools that will help organisational change toward gender equality. We describe tools that include formal legislation and mandated quotas at national or large-scale levels (eg, gender parity), techniques that increase fairness (eg, gender equity) through facilitated organisational cultural change at institutional levels, and professional development of core competencies at individual levels. This Review is not intended to be an extensive analysis of all the literature currently available on achieving gender equality in academic medicine and science, but rather, a reflection on finding multifactorial solutions.

Toward Developing a Preventive MERS-CoV Vaccine-Report from a Workshop Organized by the Saudi Arabia Ministry of Health and the International Vaccine Institute, Riyadh, Saudi Arabia, November 14-15, 2015.

Middle East respiratory syndrome (MERS) remains a serious international public health threat. With the goal of accelerating the development of countermeasures against MERS coronavirus (MERS-CoV), funding agencies, nongovernmental organizations, and researchers across the world assembled in Riyadh, Saudi Arabia, on November 14-15, 2015, to discuss vaccine development challenges. The meeting was spearheaded by the Saudi Ministry of Health and co-organized by the International Vaccine Institute, South Korea. Accelerating the development of a preventive vaccine requires a better understanding of MERS epidemiology, transmission, and pathogenesis in humans and animals. A combination of rodent and nonhuman primate models should be considered in evaluating and developing preventive and therapeutic vaccine candidates. Dromedary camels should be considered for the development of veterinary vaccines. Several vaccine technology platforms targeting the MERS-CoV spike protein were discussed. Mechanisms to maximize investment, provide robust data, and affect public health are urgently needed.

Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes.

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.

Transient corticosteroid treatment permanently amplifies the Th2 response in a murine model of asthma.

Corticosteroids (CS) remain the most efficacious pharmacotherapeutic option for the management of asthma. Although the acute anti-inflammatory effects of CS treatment have been amply documented both clinically and experimentally, recent human data intimate that exposure to CS may be associated with retrograde immune phenomena, including enhanced synthesis of IgE in vivo and elevated Th2 cytokine production in vitro. We have investigated the long-term immunologic effects of CS treatment in a murine model of allergic airway inflammation. CS treatment during initial exposure to OVA or upon long-term Ag rechallenge remarkably attenuated eosinophilic airway inflammation and airway hyperresponsiveness. Interestingly, however, Th2 cytokine production by cultured splenocytes from CS-treated mice was significantly elevated, while IFN-gamma synthesis was depressed. Moreover, mice rechallenged with OVA several weeks after CS intervention during allergic sensitization not only developed airway inflammation, but also exhibited enhanced Th2 cytokine production in lymphoid tissues and OVA-specific IgE in serum. This amplification of the systemic immune response was associated with an intact APC compartment during CS-conditioned sensitization to OVA. These data indicate that immune processes underlying the allergic phenotype remain impervious to CS treatment and raise the possibility that treatment with CS during sensitization may amplify elements of the allergen-specific immune response.

Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling.

It is now fully appreciated that asthma is a disease of a chronic nature resulting from intermittent or continued aeroallergen exposure leading to airway inflammation. To investigate responses to continuous antigen exposure, mice were exposed to either house dust mite extract (HDM) or ovalbumin intranasally for five consecutive days, followed by 2 days of rest, for up to seven consecutive weeks. Continuous exposure to HDM, unlike ovalbumin, elicited severe and persistent eosinophilic airway inflammation. Flow cytometric analysis demonstrated an accumulation of CD4+ lymphocytes in the lung with elevated expression of inducible costimulator a marker of T cell activation, and of T1/ST2, a marker of helper T Type 2 effector cells. We also detected increased and sustained production of helper T cell Type 2-associated cytokines by splenocytes of HDM-exposed mice on in vitro HDM recall. Histologic analysis of the lung showed evidence of airway remodeling in mice exposed to HDM, with goblet cell hyperplasia, collagen deposition, and peribronchial accumulation of contractile tissue. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. Finally, these responses were studied for up to 9 weeks after cessation of HDM exposure. We observed that whereas airway inflammation resolved fully, the remodeling changes did not resolve and airway hyperreactivity resolved only partly.

GM-CSF and dendritic cells in allergic airway inflammation: basic mechanisms and prospects for therapeutic intervention.

The interaction between dendritic cells (DC) and naïve T cells is the first step in the evolution of an immune response, either tolerogenic or inflammatory. Therefore, the status of DC residing at mucosal sites, such as the airway, has a definitive impact on the character of the ensuing immune response. In the absence of pathogenic stimulation, DC serve to regulate immunological homeostasis in the lung; the generation of Th2-associated (allergic) inflammatory responses, which are directed at presumably innocuous antigens, represent a deviation from normal DC function. The dysregulation of DC phenotype leading to the development of allergy might be programmed by genetic pedigree, or might be induced by factors released in the airway. One potential candidate, GM-CSF, is abundant in the allergic airway and can condition DC to propagate Th2 responses. Moreover, that allergens, alone or in combination with other factors, can spontaneously induce GM-CSF production in the airway thus present a compelling etiological argument for the role of GM-CSF in allergic sensitization. The interplay between DC and mediators present in the allergic airway is likely critical to the establishment of allergic airway inflammation. Understanding these interactions may, therefore, afford insight into prospective therapeutic interventions to circumvent, and even reverse the allergic diathesis.

Evaluation of inducible costimulator/B7-related protein-1 as a therapeutic target in a murine model of allergic airway inflammation.

Given its primary role in the execution of T cell, and especially Th2, effector activity, the inducible costimulator (ICOS)/B7-related protein (RP)-1 costimulatory pathway is currently being heralded as a promising therapeutic target for immune-inflammatory disorders such as asthma. This study investigates the merits of ICOS blockade in a murine model of experimental asthma in which mice are sensitized to ovalbumin (OVA) through the respiratory mucosa. Intraperitoneal treatment of mice with anti-ICOS neutralizing antibody during sensitization resulted in a marked reduction in airway eosinophilia and IL-5 in bronchoalveolar lavage, but had no effect on interleukin (IL)-4, IL-13, and eotaxin content in bronchoalveolar lavage or the production of OVA-specific immunoglobulin E in serum. Cultured splenocytes from mice sensitized to OVA in the context of ICOS ablation produced enhanced levels of IL-4 and IL-5 upon stimulation with OVA, and this correlated with elevated inflammation and immunoglobulin E secretion upon long-term in vivo OVA recall; the deleterious effects ICOS blockade, however, were not associated with reduced IL-10 production by splenocytes. Peculiarly, anti-ICOS intervention during OVA rechallenge had no effect on airway inflammation or immunoglobulin production, despite high levels of ICOS expression on infiltrating CD4+ T cells. This study provides in vivo evidence of an exacerbated long-term immune-inflammatory response following acute ICOS blockade, and suggests that ICOS costimulation is functionally redundant in established allergic disease.