Digital financial services for health in support of universal health coverage: qualitative programmatic case studies from Kenya and Rwanda.

BACKGROUND: This document describes two qualitative programmatic case studies documenting experiences implementing digital financial services (DFS) for health with a focus on expanding access to universal health coverage (UHC). The CBHI 3MS system in Rwanda and the i-PUSH and Medical Credit Fund programs in Kenya were selected because they represent innovative use of digital financing technologies to support UHC programs at scale. METHODS: These studies were conducted from April-August 2021 as part of a broader digital financial services landscape assessment that used a mixed methods process evaluation to answer three questions: 1) what was the experience implementing the program, 2) how was it perceived to influence health systems performance, and 3) what was the client/beneficiary experience? Qualitative interviews involved a range of engaged stakeholders, including implementers, developers, and clients/users from the examined programs in both countries. Secondary data were used to describe key program trends. RESULTS: Respondents agreed that DFS contributed to health system performance by making systems more responsive, enabling programs to implement changes to digital services based on new laws or client-proposed features, and improving access to quality data for better management and improved quality of services. Key informants and secondary data confirmed that both implementations likely contributed to increasing health insurance coverage; however, other changes in market dynamics were also likely to influence these changes. Program managers and some beneficiaries praised the utility of digital functions, compared to paper-based systems, and noted their effect on individual savings behavior to contribute to household resilience. DISCUSSION/CONCLUSIONS: Several implementation considerations emerged as facilitators or barriers to successful implementation of DFS for health, including the importance of multisectoral investments in general ICT infrastructure, the value of leveraging existing community resources (CHWs and mobile money agents) to boost enrollment and help overcome the digital divide, and the significance of developing trust across government and private sector organizations. The studies led to the development of five main recommendations for the design and implementation of health programs incorporating DFS.

Unit costs of needle and syringe program provision: a global systematic review and cost extrapolation.

BACKGROUND: Needle and syringe programs (NSPs) are effective at preventing HIV and hepatitis C virus (HCV) among people who inject drugs (PWID), yet global coverage is low, partly because governments lack data on the cost and cost-effectiveness of NSP in their countries to plan and fund their responses. We conducted a global systematic review of unit costs of NSP provision to inform estimation of cost drivers and extrapolated costs to other countries. METHODS: We conducted a systematic review to extract data on the cost per syringe distributed and its cost drivers. We estimated the impact of country-level and program-level variables on the cost per syringe distributed using linear mixed-effects models. These models were used to predict unit costs of NSP provision, with the best performing model used to extrapolate the cost per syringe distributed for 137 countries. The total cost for a comprehensive NSP (200 syringes per PWID/year) was also estimated for 68 countries with PWID population size estimates. RESULTS: We identified 55 estimates of the unit cost per syringe distributed from 14 countries. Unit costs were extrapolated for 137 countries, ranging from $0.08 to $20.77 (2020 USD) per syringe distributed. The total estimated spend for a high-coverage, comprehensive NSP across 68 countries with PWID size estimates is $5 035 902 000 for 10 887 500 PWID, 2.1-times higher than current spend. CONCLUSION: Our review identified cost estimates from high-income, upper-middle-income, and lower-middle-income countries. Regression models may be useful for estimating NSP costs in countries without data to inform HIV/HCV prevention programming and policy.

Learning from the past to plan for the future: An historical review of the evolution of waste and resource management 1970-2020 and reflections on priorities 2020-2030 - The perspective of an involved witness.

Improving waste and resource management (WaRM) around the world can halve the weight of plastics entering the oceans, significantly mitigate global heating and contribute directly to 12 of 17 sustainable development goals (SDGs). Achieving such results demands understanding and learning from historical evolution of WaRM. The baseline is 1970, prior to environmental legislation. Early steps in the Global North focused on the 'technical fix' within strictly enforced legal frameworks, first bringing hazardous wastes and municipal solid wastes (MSW) under control, then gradually ramping up environmental standards. Using modern technologies to the Global South often failed due to institutional and financial constraints. From 1990, focus switched to integrating technical and governance aspects: local institutional coherence, financial sustainability, provider inclusivity, user inclusivity, national legislative and policy framework. The Global North rediscovered recycling, using policy measures to promote segregation at source; this relied on new markets in emerging economies, which had largely disappeared by 2020. The Global South is making progress on bringing wastes under control, but around 2.7 billion people lack access to waste collection, while ~40% of collected MSW is open dumped or burned - a continuing global waste emergency. So, much remains to be done to move further towards a circular economy. Three policy priorities are critical for all countries: access to sustainable financing, rethinking sustainable recycling and worldwide extended producer responsibility with teeth. Extending services to unserved communities (SDG11.6.1) requires a people-centred approach, working with communities to provide both quality services and decent livelihoods for collection and recycling workers.

Device safety assessment of bronchoscopic microwave ablation of normal swine peripheral lung using robotic-assisted bronchoscopy.

INTRODUCTION: The aim of this study was to assess the safety of bronchoscopic microwave ablation (MWA) of peripheral lung parenchyma using the NEUWAVE™ FLEX Microwave Ablation System, and robotic-assisted bronchoscopy (RAB) using the MONARCH™ Platform in a swine model. METHODS: Computed tomography (CT)-guided RAB MWA was performed in the peripheral lung parenchyma of 17 Yorkshire swine (40-50 kg) and procedural adverse events (AEs) documented. The acute group (day 0, n = 5) received 4 MWAs at 100 W for 1, 3, 5, and 10 min in 4 different lung lobes. Subacute and chronic groups (days 3 and 30, n = 6 each) received one MWA (100 W, 10 min) per animal. RESULTS: The study was completed without major procedural complications. No postprocedural AEs including death, pneumothorax, bronchopleural fistula, hemothorax, or pleural effusions were observed. No gross or histological findings suggestive of thromboembolism were found in any organ. One 3-Day and one 30-Day swine exhibited coughing that required no medication (minor AEs), and one 30-Day animal required antibiotic medication (major AE) for a suspected lower respiratory tract infection that subsided after two weeks. CT-based volumetric estimates of ablation zones in the acute group increased in an ablation time-dependent (1-10 min) manner, whereas macroscopy-based estimates showed an increasing trend in ablation zone size. CONCLUSION: The NEUWAVE FLEX and MONARCH devices were safely used to perform single or multiple RAB MWAs. The preclinical procedural safety profile of RAB MWA supports clinical research of both devices to investigate efficacy in select patients with oligometastatic disease or primary NSCLC.

Socio-economic development drives solid waste management performance in cities: A global analysis using machine learning.

Mismanaged municipal solid waste (MSW), the major source of plastics pollution and a key contributor to climate forcing, in Global South cities poses public health and environmental problems. This study analyses the first consistent and quality assured dataset available for cities distributed worldwide, featuring a comprehensive set of solid waste management performance indicators (Wasteaware Cities Benchmark Indicators - WABI). Machine learning (multivariate random forest) and univariate non-linear regression are applied, identifying best-fit converging models for a broad range of explanatory socioeconomic variables. These proxies describe in a variety of ways generic levels of progress, such as Gross Domestic Product - Purchasing Power per capita, Social Progress Index (SPI) and Corruption Perceptions Index. Specifically, the research tests and quantitatively confirms a long-standing, yet unverified, hypothesis: that variability in cities' performance on MSW can be accounted for by socioeconomic development indices. The results provide a baseline for measuring progress as cities report MSW performance for the sustainable development goal SDG11.6.1 indicator: median rates of controlled recovery and disposal are approximately at 45 % for cities in low-income countries, 75 % in lower-middle, and 100 % for both upper-middle and high-income. Casting light on aspects beyond the SDG metric, on the quality of MSW-related services, show that improvements in service quality often lag improvements in service coverage. Overall, the findings suggest that progress in collection coverage, and controlled recovery and disposal has already taken place in low- and middle-income cities. However, if cities aspire to perform better on MSW management than would have been anticipated by the average socioeconomic development in their country, they should identify ways to overcome systemic underlying failures associated with that socioeconomic level. Most alarmingly, 'business as usual' development would substantially increase their waste generation per capita unless new policies are found to promote decoupling.

Assessment of therapeutic role of mesenchymal stromal cells in mouse models of graft-versus-host disease using cryo-imaging.

Insights regarding the biodistribution and homing of mesenchymal stromal cells (MSCs), as well as their interaction with alloreactive T-cells are critical for understanding how MSCs can regulate graft-versus-host disease (GVHD) following allogeneic (allo) bone marrow transplantation (BMT). We developed novel assays based on 3D, microscopic, cryo-imaging of whole-mouse-sized volumes to assess the therapeutic potential of human MSCs using an established mouse GVHD model. Following infusion, we quantitatively tracked fluorescently labeled, donor-derived, T-cells and third party MSCs in BMT recipients using multispectral cryo-imaging. Specific MSC homing sites were identified in the marginal zones in the spleen and the lymph nodes, where we believe MSC immunomodulation takes place. The number of MSCs found in spleen of the allo BMT recipients was about 200% more than that observed in the syngeneic group. To more carefully define the effects MSCs had on T cell activation and expansion, we developed novel T-cell proliferation assays including secondary lymphoid organ (SLO) enlargement and Carboxyfluoescein succinimidyl ester (CFSE) dilution. As anticipated, significant SLO volume enlargement and CFSE dilution was observed in allo but not syn BMT recipients due to rapid proliferation and expansion of labeled T-cells. MSC treatment markedly attenuated CFSE dilution and volume enlargement of SLO. These assays confirm evidence of potent, in vivo, immunomodulatory properties of MSC following allo BMT. Our innovative platform includes novel methods for tracking cells of interest as well as assessing therapeutic function of MSCs during GVHD induction. Our results support the use of MSCs treatment or prevention of GVHD and illuminate the wider adoption of MSCs as a standard medicinal cell therapy.

How to do (or not to do) health resource allocations using constrained mathematical optimization.

Despite the push towards evidence-based health policy, decisions about how to allocate health resources are all too often made on the basis of political forces or a continuation of the status quo. This results in wastage in health systems and loss of potential population health. However, if health systems are to serve people best, then they must operate efficiently and equitably, and appropriate valuation methods are needed to determine how to do this. With the advances in computing power over the past few decades, advanced mathematical optimization algorithms can now be run on personal computers and can be used to provide comprehensive, evidence-based recommendations for policymakers on how to prioritize health spending considering policy objectives, interactions of interventions, real-world system constraints and budget envelopes. Such methods provide an invaluable complement to traditional or extended cost-effectiveness analyses or league tables. In this paper, we describe how such methods work, how policymakers and programme managers can access them and implement their recommendations and how they have changed health spending in the world to date.

Cost optimisation analysis of the expanded programme for immunisation: balancing equity and coverage in Pakistan.

INTRODUCTION: With limited resources, attaining maximal average health service coverage can be at odds with maximising equity which attempts to promote greater reach among underserved populations. In this study, we examined the trade-offs in immunisation coverage levels and equity for children under 5 years of age in Pakistan across various subpopulations who can be targeted with different combinations of immunisation service modalities. METHODS: We conducted a detailed costing exercise across 16 geographically and demographically diverse districts in Pakistan. These data were the basis for (a) technical efficiency benchmarking via Data Envelopment Analysis to identify potential efficiency gains by location, delivery model and cost ingredient; (b) allocative efficiency optimisation modelling to understand how resource allocations could be optimised and to devise recommended budget allocations and operational metrics. Finally, the hypothetical overall efficiency gains attainable were estimated if available resources were allocated with the optimal emphases, and if service delivery models operated at productivity levels at the benchmarked frontier of efficiency. RESULTS: Benchmarking suggests that ~44% of delivery models are running efficiently and 37% are highly inefficient. While coverage and equity are usually at odds, surprisingly, the optimisation modelling revealed that substantial improvements in equity between subpopulations does not necessarily cost very much in overall immunisation coverage: theoretically, equity can be achieved while still attaining close to maximal immunisation coverage. Overall, analyses suggest greater emphases should be placed on outreach delivery models which particularly target rural areas and slum populations. CONCLUSION: The unit cost differentials within districts are not sufficiently large for there to be a large reduction in potential Fully Immunised Children coverage if one focuses on maximising equity. However, reallocations of programme budgets can have a significant impact on equity outcomes, particularly at current low spending amounts. Therefore, it is recommended to address equity as the key objective in national immunisation programming.

The impact of financial incentives on HIV incidence among adolescent girls and young women in Eswatini: Sitakhela Likusasa, a cluster randomised trial.

INTRODUCTION: Incentives conditional on school attendance or on remaining free of sexually transmitted infections have produced mixed results in reducing HIV incidence. METHODS: HIV-negative adolescent girls and young women aged 15-22%-50% of whom were out of school-were recruited from 293 clusters in Eswatini from urban (30%) and rural areas (70%).Financial incentives conditional on education attendance were randomly allocated at the cluster level. All participants were further individually randomised into eligibility for a raffle incentive conditional on random selection into the raffle, on negative tests for syphilis and Trichomonas vaginalis and on being a raffle winner, creating four subarms in a 2×2 factorial design: no-intervention, raffle incentive, education incentive and raffle & education incentive. Randomisation was unblinded to participants.Logistic regressions were used in intention-to-treat analysis of HIV incidence over 3 years to estimate the impact of incentives conditional on school attendance and raffle incentives conditional on remaining sexually transmitted infection free. RESULTS: The study recruited 4389 HIV-negative participants, who were distributed into four subarms: no intervention (n=1068), raffle incentive (n=1162), education incentive (n=1088) and raffle and education incentive (n=1071).At endline, 272 participants from 3772 for whom endline data were collected, tested positive for HIV. HIV incidence among participants in education treatment arm was significantly lower than in the education control arm, 6.34% (119/1878) versus 8.08% (153/1894) (p=0.041); OR: 0.766 (0.598 to 0.981); adjusted OR (aOR): 0.754 (0.585 to 0.972). Compared with the no intervention subarm, HIV incidence in the raffle and education incentive subarm was significantly lower, 5.79% (54/878) versus 8.84% (80/905); OR: 0.634 (0.443 to 0.907); aOR: 0.622 (0.433 to 0.893), while it was not significantly lower in the raffle incentive subarm. CONCLUSION: Financial incentives conditional on education participation significantly reduced HIV infection among adolescent girls and young women in Eswatini and appear to be a promising tool for prevention in high HIV prevalence settings. TRIAL REGISTRATION NUMBER: Western Institutional Review Board-protocol number 20 141 630.Eswatini National Health Research Review Board-FWA00026661.Pan African Clinical Trials Registry-PACTR201811609257043.

Deep Learning Segmentation, Visualization, and Automated 3D Assessment of Ciliary Body in 3D Ultrasound Biomicroscopy Images.

Purpose: This study aimed to develop a fully automated deep learning ciliary body segmentation and assessment approach in three-dimensional ultrasound biomicroscopy (3D-UBM) images. Methods: Each 3D-UBM eye volume was aligned to the optic axis via multiplanar reformatting. Ciliary muscle and processes were manually annotated, and Deeplab-v3+ models with different loss functions were trained to segment the ciliary body (ciliary muscle and processes) in both en face and radial images. Results: We trained and tested the models on 4320 radial and 3864 en face images from 12 cadaver eye volumes. Deep learning models trained on radial images with Dice loss achieved the highest mean F1-score (0.89) for ciliary body segmentation. For three-class segmentation (ciliary muscle, processes, and background), radial images with Dice loss achieved the highest mean F1-score (0.75 for the ciliary process and 0.82 for the ciliary muscle). Part of the ciliary muscle (10.9%) was misclassified as the ciliary process and vice versa, which occurred owing to the difficulty in differentiating the ciliary muscle-processes border, even by experts. Deep learning segmentation made further editing by experts at least seven times faster than a fully manual approach. In eight cadaver eyes, the average ciliary muscle, process, and body volumes were 56 ± 9, 43 ± 13, and 99 ± 18 mm3, respectively. The average surface area of the ciliary muscle, process, and body were 346 ± 45, 363 ± 83, and 709 ± 80 mm2, respectively. We performed transscleral cyclophotocoagulation in cadaver eyes to shrink the ciliary processes. Both manual and automated measurements from deep learning segmentation show a decrease in volume, surface area, and 360° cross-sectional area measurements. Conclusions: The proposed deep learning segmentation of the ciliary body and 3D measurements showed transscleral cyclophotocoagulation-related changes in the ciliary body. Translational Relevance: Automated ciliary body assessment using 3D-UBM has the translational potential for ophthalmic treatment planning and monitoring.

Cost-effectiveness and impact of pre-exposure prophylaxis to prevent HIV among men who have sex with men in Asia: A modelling study.

INTRODUCTION: More than 70% of new HIV infections in Asia occurred in eight countries in 2020: Cambodia, China, India, Indonesia, Myanmar, Nepal, Thailand, and Vietnam-with a rising incidence among men who have sex with men (MSM). The World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) for those at risk of acquiring HIV, yet wide-scale implementation of PrEP, on a daily or event-driven basis, has been limited in Asia. METHODS: The Optima HIV model was applied to examine the impact of scaling-up PrEP over five-years to cover an additional 15% of MSM compared with baseline coverage, a target deemed feasible by regional experts. Based on behavioral survey data, we assume that covering 15% of higher-risk MSM will cover 30% of all sexual acts in this group. Scenarios to compare the impact of generic-brand daily dosing of PrEP with generic event-driven dosing (15 days a month) were modelled from the start of 2022 to the end of 2026. Cost-effectiveness of generic versus branded PrEP was also assessed for China, the only country with an active patent for branded, higher cost PrEP. The impact on new HIV infections among the entire population and cost per HIV-related disability-adjusted life year (DALY) averted were estimated from the beginning of 2022 to the end of 2031 and from 2022 to 2051. RESULTS: If PrEP were scaled-up to cover an additional 15% of MSM engaging in higher-risk behavior from the beginning of 2022 to the end of 2026 in the eight Asian countries considered, an additional 100,000 (66,000-130,000) HIV infections (17%) and 300,000 (198,000-390,000) HIV-related DALYs (3%) could be averted over the 2022 to 2031 period. The estimated cost per HIV-related DALY averted from 2022 to 2031 ranged from US$600 for event-driven generic PrEP in Indonesia to US$34,400 for daily branded PrEP in Thailand. Over a longer timeframe from 2022 to 2051, the cost per HIV-related DALY averted could be reduced to US$100-US$12,700. CONCLUSION: PrEP is a critical tool to further reduce HIV incidence in highly concentrated epidemics. Implementing PrEP in Asia may be cost-effective in settings with increasing HIV prevalence among MSM and if PrEP drug costs can be reduced, PrEP could be more cost-effective over longer timeframes.

Assessment of Post-Dilatation Strategies for Optimal Stent Expansion in Calcified Coronary Lesions: Ex Vivo Analysis With Optical Coherence Tomography.

INTRODUCTION: Interventional cardiologists make adjustments in the presence of coronary calcifications known to limit stent expansion, but proper balloon sizing, plaque-modification approaches, and high-pressure regimens are not well established. Intravascular optical coherence tomography (IVOCT) provides high-resolution images of coronary tissues, including detailed imaging of calcifications, and accurate measurements of stent deployment, providing a means for detailed study of stent deployment. OBJECTIVE: Evaluate stent expansion in an ex vivo model of calcified coronary arteries as a function of balloon size and high-pressure, post-dilatation strategies. METHODS: We conducted experiments on cadaver hearts with calcified coronary lesions. We assessed stent expansion as a function of size and pressure of non-compliant (NC) balloons (i.e., nominal, 0.5, 1.0, and 1.5 mm balloons at 10, 20 and 30 atm). IVOCT images were acquired pre-stent, post-stent, and at all post-dilatations. Stent expansion was calculated using minimum expansion index (MEI). RESULTS: We analyzed 134 IVOCT pullbacks from ten ex-vivo experiments. The mean distal and proximal reference lumen diameters were 2.2 ± 0.5 mm and 2.5 ± 0.7 mm, respectively, 80% of times using a 3.0 mm diameter stent. Overall, based on stent sizing, a good expansion (MEI ≥ 80%) was reached using the 1:1 NC balloon at 20 atm, and expansion > 100% was reached using the 1:1 NC balloon at 30 atm. In the subgroup analysis, comparing low-calcified and high-calcified lesions, good expansion (MEI ≥ 80%) was reached using the 1:1 NC balloon at nominal pressure (10 atm) versus using 1:1 NC balloon at 30 atm, respectively. Significant vessel rupture was identified in all the vessels mainly upon post-dilatation with larger balloons, and 60% of the experiments (6 vessels, 3 in each calcium subgroup) presented rupture with the +1.0 mm NC balloon at 20 atm. CONCLUSION: When treating calcified lesions, good stent expansion was reached using smaller balloons at higher pressures without coronary injuries, whereas bigger balloons yielded unpredictable expansion even at lower pressures and demonstrated potential harmful damages to the vessels. As these findings could help physicians with appropriate planning of stent post-dilatation for calcified lesions, it will be important to clinically evaluate the recommended protocol.

Clinical Assessment of Deep Learning-based Super-Resolution for 3D Volumetric Brain MRI.

Artificial intelligence (AI)-based image enhancement has the potential to reduce scan times while improving signal-to-noise ratio (SNR) and maintaining spatial resolution. This study prospectively evaluated AI-based image enhancement in 32 consecutive patients undergoing clinical brain MRI. Standard-of-care (SOC) three-dimensional (3D) T1 precontrast, 3D T2 fluid-attenuated inversion recovery, and 3D T1 postcontrast sequences were performed along with 45% faster versions of these sequences using half the number of phase-encoding steps. Images from the faster sequences were processed by a Food and Drug Administration-cleared AI-based image enhancement software for resolution enhancement. Four board-certified neuroradiologists scored the SOC and AI-enhanced image series independently on a five-point Likert scale for image SNR, anatomic conspicuity, overall image quality, imaging artifacts, and diagnostic confidence. While interrater κ was low to fair, the AI-enhanced scans were noninferior for all metrics and actually demonstrated a qualitative SNR improvement. Quantitative analyses showed that the AI software restored the high spatial resolution of small structures, such as the septum pellucidum. In conclusion, AI-based software can achieve noninferior image quality for 3D brain MRI sequences with a 45% scan time reduction, potentially improving the patient experience and scanner efficiency without sacrificing diagnostic quality. Keywords: MR Imaging, CNS, Brain/Brain Stem, Reconstruction Algorithms © RSNA, 2022.

The Use of Cost-Effectiveness Thresholds for Evaluating Health Interventions in Low- and Middle-Income Countries From 2015 to 2020: A Review.

OBJECTIVES: Evidence-informed priority setting, in particular cost-effectiveness analysis (CEA), can help target resources better to achieve universal health coverage. Central to the application of CEA is the use of a cost-effectiveness threshold. We add to the literature by looking at what thresholds have been used in published CEA and the proportion of interventions found to be cost-effective, by type of threshold. METHODS: We identified CEA studies in low- and middle-income countries from the Global Health Cost-Effectiveness Analysis Registry that were published between January 1, 2015, and January 6, 2020. We extracted data on the country of focus, type of interventions under consideration, funder, threshold used, and recommendations. RESULTS: A total of 230 studies with a total 713 interventions were included in this review; 1 to 3× gross domestic product (GDP) per capita was the most common type of threshold used in judging cost-effectiveness (84.3%). Approximately a third of studies (34.2%) using 1 to 3× GDP per capita applied a threshold at 3× GDP per capita. We have found that no study used locally developed thresholds. We found that 79.3% of interventions received a recommendation as "cost-effective" and that 85.9% of studies had at least 1 intervention that was considered cost-effective. The use of 1 to 3× GDP per capita led to a higher proportion of study interventions being judged as cost-effective compared with other types of thresholds. CONCLUSIONS: Despite the wide concerns about the use of 1 to 3× GDP per capita, this threshold is still widely used in the literature. Using this threshold leads to more interventions being recommended as "cost-effective." This study further explore alternatives to the 1 to 3× GDP as a decision rule.

Technology and Universal Health Coverage: Examining the role of digital health.

While there is tremendous promise to leverage technology for UHC, it will require smart, context-specific policies and programming with ample flexibility to adapt as needs and opportunities change - and with robust safeguards to protect privacy, data security, and equity. The health sector, by its very nature of being data intensive, lends itself to the use of technology for analytics to improve health outcomes, respond to public health crises, and efficiently and equitably allocate resources. The first imperative in considering the use of digital health to expand UHC is to remember that digital health is a means to an end, and only one of the available means. Efforts leveraging digital health to move along that path to universality have taken many forms: to increase the number of people reached, to provide enhanced service coverage, and to reduce the financial burdens on individuals in need of health care. Making use of digital health interventions is an evolving process, not a one-time decision point. It is context specific and needs a clear vision to move from pilot interventions to scaled implementation. Technology can be a key tool in achieving UHC but its use has to be strategic, judicious, and cognizant of issues around privacy and patient rights.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [89Zr]DFB(25) NPs and [89Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.

Open MRI assessment of anterior femoroacetabular clearance in active and passive impingement-provoking postures.

AIMS: Cam and pincer morphologies are potential precursors to hip osteoarthritis and important contributors to non-arthritic hip pain. However, only some hips with these pathomorphologies develop symptoms and joint degeneration, and it is not clear why. Anterior impingement between the femoral head-neck contour and acetabular rim in positions of hip flexion combined with rotation is a proposed pathomechanism in these hips, but this has not been studied in active postures. Our aim was to assess the anterior impingement pathomechanism in both active and passive postures with high hip flexion that are thought to provoke impingement. METHODS: We recruited nine participants with cam and/or pincer morphologies and with pain, 13 participants with cam and/or pincer morphologies and without pain, and 11 controls from a population-based cohort. We scanned hips in active squatting and passive sitting flexion, adduction, and internal rotation using open MRI and quantified anterior femoroacetabular clearance using the ß angle. RESULTS: In squatting, we found significantly decreased anterior femoroacetabular clearance in painful hips with cam and/or pincer morphologies (mean -11.3° (SD 19.2°)) compared to pain-free hips with cam and/or pincer morphologies (mean 8.5° (SD 14.6°); p = 0.022) and controls (mean 18.6° (SD 8.5°); p < 0.001). In sitting flexion, adduction, and internal rotation, we found significantly decreased anterior clearance in both painful (mean -15.2° (SD 15.3°); p = 0.002) and painfree hips (mean -4.7° (SD 13°); p = 0.010) with cam and/pincer morphologies compared to the controls (mean 7.1° (SD 5.9°)). CONCLUSION: Our results support the anterior femoroacetabular impingement pathomechanism in hips with cam and/or pincer morphologies and highlight the effect of posture on this pathomechanism. Cite this article: Bone Jt Open 2021;2(11):988-996.