Costs of care and financial hardship among patients with heart failure.

With the implementation of new therapies, more patients are living with heart failure (HF) as a chronic condition. Alongside these advances, out-of-pocket (OOP) medical costs have increased, and patients experience significant financial burden. Despite increasing interest in understanding and mitigating financial burdens, there is a relative paucity of data specific to HF. Here, we explore financial hardship in HF from the patient perspective, including estimated OOP costs for guideline-directed medical therapy for HF with reduced ejection fraction, hospitalizations, and total direct medical costs, as well as the consequences of high OOP costs. Studies estimate that high OOP costs are common in HF, and a large proportion are related to prescription drugs. Subsequently, the effects on patients can lead to worsening adherence, delayed care, and poor outcomes, leading to a financial toxicity spiral. Further, we summarize patients' cost preferences and outline future research that is needed to develop evidence-based solutions to reduce costs in HF.

Guideline Adherence and Practice Patterns in the Management of Medullary Thyroid Cancer.

INTRODUCTION: Little is known about nationwide practice patterns for the management medullary thyroid cancer (MTC) in relation to the 2015 American Thyroid Association guidelines and their impact on survival. METHODS: Using the Surveillance, Epidemiology, and End Results Program database (2000-2018), MTC treatment patterns were evaluated in terms of adherence to the 2015 American Thyroid Association guidelines across three time periods (2000-2009, 2010-2015, and 2016-2018). Outcomes of interest were guideline concordance, treatment utilization trends, disease-specific survival (DSS), and overall survival (OS). RESULTS: A total of 3332 patients with MTC were identified. Of which, 53.8%, 33.2%, and 11.4% of patients had localized, regional, and distant disease, respectively. In patients with locoregional disease, the rate of guideline-concordant surgery improved over time from 63.0% in 2000-2009 to 76.0% in 2016-2018 (P < 0.001). Guideline-concordant care was associated with increased OS (HR = 1.85, 95% CI: 1.42-2.43, P < 0.001) in patients with localized disease and increased DSS (HR = 1.65, 95% CI: 1.01-2.54, P < 0.001) and OS (HR = 1.89, 95% CI: 1.35-2.58, P < 0.001) in patients with regional disease. The median OS and DSS in patients with distant disease were 31 and 55 mo, respectively, and the rate of chemotherapy use rose from 21.6% to 39.2% (P = 0.003). CONCLUSIONS: The rate of guideline-concordant surgery for locoregional MTC increased after guideline publication in 2015, with an observed prolongment in OS and DSS. Chemotherapy use among patients with distant disease has increased over time, but their prognosis remains variable.

Implementation of an educational intervention to improve medical student cost awareness: a prospective cohort study.

BACKGROUND: In the context of rising healthcare costs, formal education on treatment-related financial hardship is lacking in many medical schools, leaving future physicians undereducated and unprepared to engage in high-value care. METHOD: We performed a prospective cohort study to characterize medical student knowledge regarding treatment-related financial hardship from 2019 to 2020 and 2020-2021, with the latter cohort receiving a targeted educational intervention to increase cost awareness. Using Kirkpatrick's four-level training evaluation model, survey data was analyzed to characterize the acceptability of the intervention and the impact of the intervention on student knowledge, attitudes, and self-reported preparedness to engage in cost-conscious care. RESULTS: Overall, N = 142 medical students completed the study survey; 61 (47.3%) in the non-intervention arm and 81 (66.4%) in the intervention arm. Of the 81 who completed the baseline survey in the intervention arm, 65 (80.2%) completed the immediate post-intervention survey and 39 (48.1%) completed the two-month post-intervention survey. Following the educational intervention, students reported a significantly increased understanding of common financial terms, access to cost-related resources, and level of comfort and preparedness in engaging in discussions around cost compared to their pre-intervention responses. The majority of participants (97.4%) reported that they would recommend the intervention to future students. A greater proportion of financially stressed students reported considering patient costs when making treatment decisions compared to their non-financially stressed peers. CONCLUSIONS: Targeted educational interventions to increase cost awareness have the potential to improve both medical student knowledge and preparedness to engage in cost-conscious care. Student financial stress may impact high-value care practices. Robust curricula on high-value care, including treatment-related financial hardship, should be formalized and universal within medical school training.

Navigating the high costs of cancer care: opportunities for patient engagement.

Over the past decade, the financial burden of cancer care on patients and their families has garnered increased attention. Many of the potential solutions have focused on system-level interventions such as adopting value-based payment models and negotiating drug prices; less consideration has been given to actions at the patient level to address cancer care costs. We argue that it is imperative to develop and support patient-level strategies that engage patients and consider their preferences, values and individual circumstances. Opportunities to meet these aims and improve the economic experience of patients in oncology are discussed, including: shared decision-making and communication, financial navigation and treatment planning, digital technology and alternative care pathways, and value-based insurance design.

Lay abstract The financial burden of cancer care on patients and their families is a growing problem and action is critically needed to alleviate the high costs of such care. So far, potential solutions have focused on system-level interventions, with less consideration given to solutions at the patient level. This review argues that it is imperative to develop and support patient-level strategies that engage patients. Next, the review presents evidence of the interplay between patient preferences and values and the costs of cancer care. Finally, opportunities to enhance engagement and improve the economic experience of patients in oncology are discussed, including: shared decision-making and communication, financial navigation and treatment planning, digital technology and alternative care pathways, and value-based insurance design.

Recurrent Laryngeal Nerve Injury After Thyroid Surgery: An Analysis of 11,370 Patients.

BACKGROUND: Recurrent laryngeal nerve (RLN) injury is a well-known, potentially serious complication of thyroid surgery. We investigated factors associated with RLN injury during thyroid surgery using a multi-institutional data set. MATERIALS AND METHODS: Patients who underwent either lobectomy or total thyroidectomy were abstracted from the American College of Surgeons National Surgical Quality Improvement Program thyroidectomy-specific database (2016-2017). Baseline and operative factors associated with RLN injury ≤30 d of surgery were analyzed using bivariate and multivariate methods. Secondary complications of interest included unplanned reintubation and hypocalcemia. RESULTS: RLN injury occurred in 6.0% (n = 677) of the 11,370 patients included in the study. The RLN injury rate varied significantly based on the primary indication for surgery, from 4.3% in patients undergoing surgery for a single nodule to 9.0% in patients undergoing surgery for differentiated cancer (P < 0.01). RLN injury occurred more often in thyroidectomies than lobectomies (6.9% versus 4.3%, P < 0.01) and in surgeries without intraoperative nerve monitoring (6.5% versus 5.6%, P = 0.01). After multivariate adjustment, RLN injury was independently associated with age ≥65 y [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.3-2.0], total thyroidectomy (OR = 1.4, 95% CI 1.1-1.6), and diagnosis of thyroid malignancy (OR = 2.1, 95% CI = 1.6-2.7) (all P < 0.001) but not intraoperative RLN monitoring (OR = 0.9, 95% CI = 0.7-1.0, P = 0.06). CONCLUSIONS: In this large multi-institutional study, RLN injury ≤30 d of surgery occurred in nearly 6% of thyroid surgeries. This comprehensive analysis of RLN injury can be used to guide informed consent discussions and aid surgeons in identifying candidates who may be at higher risk for injury.

Ovarian tissue transport to expand access to fertility preservation: from animals to clinical practice.

Primordial follicles dictate a female's reproductive life span and therefore are central to fertility preservation for both endangered species and individuals with fertility-threatening conditions. Ovarian tissue containing primordial follicles can be cryopreserved and later thawed and transplanted back into individuals to restore both endocrine function and fertility. Importantly, increasing numbers of human live births have been reported following ovarian tissue cryopreservation and transplantation. A current limitation of this technology is patient access to sites that are approved or equipped to process and cryopreserve ovarian tissue - especially in larger countries or low resource settings. Here, we review empirical evidence from both animal models and human studies that suggest that ovarian tissue can be transported at cold temperatures for several hours while still maintaining the integrity and reproductive potential of the primordial follicles within the tissue. In fact, several human live births have been reported in European countries using tissue that was transported at cold temperatures for up to 20 h before cryopreservation and transplantation. Ovarian tissue transport, if implemented widely in clinical practice, could therefore expand both patient and provider access to emerging fertility preservation options.

Pain coping skills training for African Americans with osteoarthritis (STAART): study protocol of a randomized controlled trial.

BACKGROUND: African Americans bear a disproportionate burden of osteoarthritis (OA), with higher prevalence rates, more severe pain, and more functional limitations. One key barrier to addressing these disparities has been limited engagement of African Americans in the development and evaluation of behavioral interventions for management of OA. Pain Coping Skills Training (CST) is a cognitive-behavioral intervention with shown efficacy to improve OA-related pain and other outcomes. Emerging data indicate pain CST may be a promising intervention for reducing racial disparities in OA symptom severity. However, there are important gaps in this research, including incorporation of stakeholder perspectives (e.g. cultural appropriateness, strategies for implementation into clinical practice) and testing pain CST specifically among African Americans with OA. This study will evaluate the effectiveness of a culturally enhanced pain CST program among African Americans with OA. METHODS/DESIGN: This is a randomized controlled trial among 248 participants with symptomatic hip or knee OA, with equal allocation to a pain CST group and a wait list (WL) control group. The pain CST program incorporated feedback from patients and other stakeholders and involves 11 weekly telephone-based sessions. Outcomes are assessed at baseline, 12 weeks (primary time point), and 36 weeks (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include self-efficacy, pain coping, pain interference, quality of life, depressive symptoms, and global assessment of change. Linear mixed models will be used to compare the pain CST group to the WL control group and explore whether participant characteristics are associated with differential improvement in the pain CST program. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill, Durham Veterans Affairs Medical Center, East Carolina University, and Duke University Health System. DISCUSSION: This culturally enhanced pain CST program could have a substantial impact on outcomes for African Americans with OA and may be a key strategy in the reduction of racial health disparities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02560922 , registered 9/22/2015.

Physical therapy vs. internet-based exercise training (PATH-IN) for patients with knee osteoarthritis: study protocol of a randomized controlled trial.

BACKGROUND: Physical activity improves pain and function among individuals with knee osteoarthritis (OA), but most people with this condition are inactive. Physical therapists play a key role in helping people with knee OA to increase appropriate physical activity. However, health care access issues, financial constraints, and other factors impede some patients from receiving physical therapy (PT) for knee OA. A need exists to develop and evaluate other methods to provide physical activity instruction and support to people with knee OA. This study is examining the effectiveness of an internet-based exercise training (IBET) program designed for knee OA, designed by physical therapists and other clinicians. METHODS/DESIGN: This is a randomized controlled trial of 350 participants with symptomatic knee OA, allocated to three groups: IBET, standard PT, and a wait list (WL) control group (in a 2:2:1 ratio, respectively). The study was funded by the Patient Centered Outcomes Research Institute, which conducted a peer review of the proposal. The IBET program provides patients with a tailored exercise program (based on functional level, symptoms, and current activity), video demonstrations of exercises, and guidance for appropriate exercise progression. The PT group receives up to 8 individual visits with a physical therapist, mirroring standard practice for knee OA and with an emphasis on a home exercise program. Outcomes are assessed at baseline, 4 months (primary time point) and 12 months (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include objective physical function, satisfaction with physical function, physical activity, depressive symptoms and global assessment of change. Linear mixed models will be used to compare both the IBET and standard PT groups to the WL control group, examine whether IBET is non-inferior to PT (a treatment that has an established evidence base for knee OA), and explore whether participant characteristics are associated with differential effects of IBET and/or standard PT. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill. DISCUSSION: The IBET program could be disseminated widely at relatively low cost and could be an important resource for helping patients with knee OA to adopt and maintain appropriate physical activity. This trial will provide an important evaluation of the effectiveness of this IBET program for knee OA. TRIAL REGISTRATION: NCT02312713.

Medullary thyroid cancer with RET V804M mutation: more indolent than expected?

BACKGROUND: Significant genotype-phenotype variability among multiple endocrine neoplasia type 2A patients with a RET V804M mutation has been reported. METHODS: Patients with a RET V804M mutation treated at a single center were identified (January 1996-December 2020). The baseline characteristics, operative details, pathology, biochemical, and long-term data were analyzed. RESULTS: There were 79 patients; none developed pheochromocytoma or hyperparathyroidism or died in the study period. The mean age was 41.5 years (range = 1.0-81.0 years); 46.8% were men. Of 68 surgical patients, 53 (77.9%) underwent total thyroidectomy and 15 (22.1%) underwent total thyroidectomy with central neck dissection with or without lateral neck dissection. Twenty-four patients had elevated preoperative calcitonin, of whom 12 underwent total thyroidectomy (median = 7.5; range = 5.0-237.0 pg/mL), 10 underwent total thyroidectomy + central neck dissection (median = 27.6; range = 5.1-147.0 pg/mL), and 2 underwent total thyroidectomy + central neck dissection + lateral neck dissection (median = 3182.0; range = 361.0-6003.0 pg/mL). Pathology was benign (27.9%), papillary thyroid cancer alone (1.5%), C-cell hyperplasia (23.5%), and medullary thyroid cancer (47.1%; median tumor size = 3.0 mm). Three patients had elevated calcitonin postoperatively (median follow-up time = 60.0 months). In adjusted modeling, a preoperative calcitonin >5 pg/mL was associated with having medullary thyroid cancer on final pathology (odds ratio = 13.3; 95% confidence interval, 3.2-56.3; P < .001). CONCLUSION: In this large United States cohort of surgical patients with a RET V804M mutation, most had indolent disease and were without classic multiple endocrine neoplasia type 2A features. Calcitonin >5 pg/mL may serve as a meaningful value to guide surveillance and timing of surgery.

Conformationally distinct five-coordinate heme-NO complexes of soluble guanylate cyclase elucidated by multifrequency electron paramagnetic resonance (EPR).

Soluble guanylate cyclase (sGC) is a heme-containing enzyme that senses nitric oxide (NO). Formation of a heme Fe-NO complex is essential to sGC activation, and several spectroscopic techniques, including electron paramagnetic resonance (EPR) spectroscopy, have been aimed at elucidating the active enzyme conformation. Of these, only EPR spectra (X-band ~9.6 GHz) have shown differences between low- and high-activity Fe-NO states, and these states are modeled in two different heme domain truncations of sGC, ß1(1-194) and ß2(1-217), respectively (Derbyshire et al., Biochemistry 2008, 47, 3892-3899). The EPR signal of the low-activity sGC Fe-NO complex exhibits a broad lineshape that has been interpreted as resulting from site-to-site inhomogeneity, and simulated using g strain, a continuous distribution about the principal values of a given g tensor. This approach, however, fails to account for visible features in the X-band EPR spectra as well as the g anisotropy observed at higher microwave frequencies. Herein we analyze X-, Q-, and D-band EPR spectra and show that both the broad lineshape and the spectral structure of the sGC EPR signal at multiple microwave frequencies can be simulated successfully with a superposition of only two distinct g tensors. These tensors represent different populations that likely differ in Fe-NO bond angle, hydrogen bonding, or the geometry of the amino acid residues. One of these conformations can be linked to a form of the enzyme with higher activity.

Tumor marker response to SARS-CoV-2 infection among patients with cancer.

BACKGROUND: Inflammatory responses from benign conditions can cause non-cancer-related elevations in tumor markers. The severe acute respiratory coronavirus 2 (SARS-CoV-2) induces a distinct viral inflammatory response, resulting in coronavirus disease 2019 (COVID-19). Clinical data suggest carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and cancer antigen 125 (CA 125) levels might rise in patients with COVID-19. However, available data excludes cancer patients, so little is known about the effect of COVID-19 on tumor markers among cancer patients. METHODS: We conducted a case series and identified patients with a positive SARS-CoV-2 PCR test, diagnosis of a solid tumor malignancy, and a CEA, CA 19-9, CA 125, or CA 27-29 laboratory test. Cancer patients with documented COVID-19 infection and at least one pre- and two post-infection tumor marker measurements were included. We abstracted the electronic health record for demographics, cancer diagnosis, treatment, evidence of cancer progression, date and severity of COVID-19 infection, and tumor marker values. RESULTS: Seven patients were identified with a temporary elevation of tumor marker values during the post-COVID-19 period. Elevation in tumor marker occurred within 56 days of COVID-19 infection for all patients. Tumor markers subsequently decreased at the second time point in the post-infectious period among all patients. CONCLUSION: We report temporary elevations of cancer tumor markers in the period surrounding COVID-19 infection. To our knowledge this is the first report of this phenomenon in cancer patients and has implications for clinical management and future research.

Patient-Reported Outcomes Following Total Thyroidectomy for Graves' Disease.

Background: Graves' disease accounts for ∼80% of all cases of hyperthyroidism and is associated with significant morbidity and decreased quality of life. Understanding the association of total thyroidectomy with patient-reported quality-of-life and thyroid-specific symptoms is critical to shared decision-making and high-quality care. We estimate the change in patient-reported outcomes (PROs) before and after surgery for patients with Graves' disease to inform the expectations of patients and their physicians. Methods: PROs using the MD Anderson Symptom Inventory (MDASI) validated questionnaire were collected prospectively from adult patients with Graves' disease from January 1, 2015, to November 20, 2020, on a longitudinal basis. Survey responses were categorized as before surgery (≤120 days), short term after surgery (<30 days; ST), and long term after surgery (≥30 days; LT). Negative binomial regression was used to estimate the association of select covariates with PROs. Results: Eighty-five patients with Graves' disease were included. The majority were female (83.5%); 47.1% were non-Hispanic white and 35.3% were non-Hispanic black. The median thyrotropin (TSH) value before surgery was 0.05, which increased to 0.82 in ST and 1.57 in LT. In bivariate analysis, the Total Symptom Burden Score, a composite of all patient-reported burden, significantly reduced shortly after surgery (before surgery mean of 56.88 vs. ST 39.60, p < 0.001), demonstrating improvement in PROs. Furthermore, both the Thyroid Symptoms Score, including patient-reported thermoregulation, palpitations, and dysphagia, and the Quality-of-Life Symptom Score improved in ST and LT (thyroid symptoms, before surgery 13.88 vs. ST 8.62 and LT 7.29; quality of life, before surgery 16.16 vs. ST 9.14 and LT 10.04, all p < 0.05). After multivariate adjustment, the patient-reported burden in the Thyroid Symptom Score and the Quality-of-Life Symptom Score exhibited reduction in ST (thyroid symptoms, rate ratio [RR] 0.55, confidence interval [CI]: 0.42-0.72; quality of life, RR 0.57, CI: 0.40-0.81) and LT (thyroid symptoms, RR 0.59, CI: 0.44-0.79; quality of Life, RR 0.43, CI: 0.28-0.65). Conclusions: Quality of life and thyroid-specific symptoms of Graves' patients improved significantly from their baseline before surgery to both shortly after and longer after surgery. This work can be used to guide clinicians and patients with Graves' disease on the expected outcomes following total thyroidectomy.

Structural basis for hydration dynamics in radical stabilization of bilin reductase mutants.

Heme-derived linear tetrapyrroles (phytobilins) in phycobiliproteins and phytochromes perform critical light-harvesting and light-sensing roles in oxygenic photosynthetic organisms. A key enzyme in their biogenesis, phycocyanobilin:ferredoxin oxidoreductase (PcyA), catalyzes the overall four-electron reduction of biliverdin IXalpha to phycocyanobilin--the common chromophore precursor for both classes of biliproteins. This interconversion occurs via semireduced bilin radical intermediates that are profoundly stabilized by selected mutations of two critical catalytic residues, Asp105 and His88. To understand the structural basis for this stabilization and to gain insight into the overall catalytic mechanism, we report the high-resolution crystal structures of substrate-loaded Asp105Asn and His88Gln mutants of Synechocystis sp. PCC 6803 PcyA in the initial oxidized and one-electron reduced radical states. Unlike wild-type PcyA, both mutants possess a bilin-interacting axial water molecule that is ejected from the active site upon formation of the enzyme-bound neutral radical complex. Structural studies of both mutants also show that the side chain of Glu76 is unfavorably located for D-ring vinyl reduction. On the basis of these structures and companion (15)N-(1)H long-range HMQC NMR analyses to assess the protonation state of histidine residues, we propose a new mechanistic scheme for PcyA-mediated reduction of both vinyl groups of biliverdin wherein an axial water molecule, which prematurely binds and ejects from both mutants upon one electron reduction, is required for catalytic turnover of the semireduced state.

Analysis of the health product pipeline for poverty-related and neglected diseases using the Portfolio-to-Impact (P2I) modeling tool.

Background: To estimate how much additional funding is needed for poverty-related and neglected disease (PRND) product development and to target new resources effectively, policymakers need updated information on the development pipeline and estimated costs to fill pipeline gaps. Methods: We previously conducted a pipeline review to identify candidates for 35 neglected diseases as of August 31, 2017 ("2017 pipeline"). We used the Portfolio-to-Impact (P2I) tool to estimate costs to move these candidates through the pipeline, likely launches, and additional costs to develop "missing products." We repeated this analysis, reviewing the pipeline to August 31, 2019 to get a time trend. We made a direct comparison based on the same 35 diseases ("2019 direct comparison pipeline"), then a comparison based on an expanded list of 45 diseases ("2019 complete pipeline"). Results: In the 2017 pipeline, 538 product candidates met inclusion criteria for input into the model; it would cost $16.3 billion (B) to move these through the pipeline, yielding 128 launches. In the 2019 direct comparison pipeline, we identified 690 candidates, an increase of 152 candidates from 2017; the largest increase was for Ebola.  The direct comparison 2019 pipeline yields 196 launches, costing $19.9B. In the 2019 complete pipeline, there were 754 candidates, an increase of 216 candidates from 2017, of which 152 reflected pipeline changes and 64 reflected changes in scope. The complete pipeline 2019 yields 207 launches, costing $21.0B. There would still be 16 "missing products" based on the complete 2019 pipeline; it would cost $5.5B-$14.2B (depending on product complexity) to develop these products. Conclusion: The PRNDs product development pipeline has grown by over a quarter in two years. The number of expected new product launches based on the 2019 pipeline increased by half compared to 2017; the cost of advancing the pipeline increased by a quarter.

Structure of the biliverdin radical intermediate in phycocyanobilin:ferredoxin oxidoreductase identified by high-field EPR and DFT.

The cyanobacterial enzyme phycocyanobilin:ferredoxin oxidoreductase (PcyA) catalyzes the two-step four-electron reduction of biliverdin IXalpha to phycocyanobilin, the precursor of biliprotein chromophores found in phycobilisomes. It is known that catalysis proceeds via paramagnetic radical intermediates, but the structure of these intermediates and the transfer pathways for the four protons involved are not known. In this study, high-field electron paramagnetic resonance (EPR) spectroscopy of frozen solutions and single crystals of the one-electron reduced protein-substrate complex of two PcyA mutants D105N from the cyanobacteria Synechocystis sp. PCC6803 and Nostoc sp. PCC7120 are examined. Detailed analysis of Synechocystis D105N mutant spectra at 130 and 406 GHz reveals a biliverdin radical with a very narrow g tensor with principal values 2.00359(5), 2.00341(5), and 2.00218(5). Using density-functional theory (DFT) computations to explore the possible protonation states of the biliverdin radical, it is shown that this g tensor is consistent with a biliverdin radical where the carbonyl oxygen atoms on both the A and the D pyrrole rings are protonated. This experimentally confirms the reaction mechanism recently proposed (Tu, et al. Biochemistry 2007, 46, 1484).

Future trajectories of urban drainage systems: A simple exploratory modeling approach for assessing socio-technical transitions.

In this work, we present a novel approach to explore future trajectories in urban drainage systems, emphasizing the adoption and implementation of sustainable 'nature-based' stormwater management strategies. The focus is on the development and long-term assessment of socio-technical pathways to create a multifunctional stormwater system at the city scale. The innovation is to identify and represent the socio-technical pathways by means of adoption curves for such transition processes. We combine urban planning policies and state-of-the-art urban engineering approaches with societal aspects and analyze them with traditional biophysical models (hydrologic-hydraulic sewer modeling). In doing so, different pathways from a current to a future system state are investigated under a variety of political, population and climate scenarios. Results allow for strategy screening by addressing the spatial and temporal implementation of decentralized stormwater control measures, to enable a successful transition to a sustainable future city. The model is applied to an ongoing transition of Kiruna, a city in Sweden, considering 36 different future trajectories over a transition period of 23 years. Results show that the trajectory of raingarden implementation under a sustainability policy can alleviate the adverse effects of urbanization (growth scenario). While this trajectory resulted in, for example, nearly the same sewer surcharge performance as that characterized by declining urbanization (stagnation) and a business-as-usual policy (with expected raingarden uptake rates approximately one-third lower), significantly better ecological performances (e.g. runoff treatment ratios up to 50%) are achieved.

Pipeline analysis of a vaccine candidate portfolio for diseases of poverty using the Portfolio-To-Impact modelling tool.

Background: The Portfolio-To-Impact (P2I) P2I model is a recently developed product portfolio tool that enables users to estimate the funding needs to move a portfolio of candidate health products, such as vaccines and drugs, along the product development path from late stage preclinical to phase III clinical trials, as well as potential product launches over time. In this study we describe the use of this tool for analysing the vaccine portfolio of the European Vaccine Initiative (EVI). This portfolio includes vaccine candidates for various diseases of poverty and emerging infectious diseases at different stages of development. Methods: Portfolio analyses were conducted using the existing assumptions integrated in the P2I tool, as well as modified assumptions for costs, cycle times, and probabilities of success based on EVI's own internal data related to vaccine development. Results: According to the P2I tool, the total estimated cost to move the 18 candidates currently in the EVI portfolio along the pipeline to launch would be about US $470 million, and there would be 0.69 cumulative expected launches during the period 2019-2031. Running of the model using EVI-internal parameters resulted in a significant increase in the expected product launches. Conclusions: The P2I tool's underlying assumptions could not be tested in our study due to lack of data available. Nevertheless, we expect that the accelerated clinical testing of vaccines (and drugs) based on the use of controlled human infection models that are increasingly available, as well as the accelerated approval by regulatory authorities that exists for example for serious conditions, will speed up product development and result in significant cost reduction. Project findings as well as potential future modifications of the P2I tool are discussed with the aim to improve the underlying methodology of the P2I model.