Prescriptions of opioid-containing drugs in patients with chronic cough.

BACKGROUND: Chronic cough (CC) affects about 10% of adults, but opioid use in CC is not well understood. OBJECTIVES: To determine the use of opioid-containing cough suppressant (OCCS) prescriptions in patients with CC using electronic health records. DESIGN: Retrospective cohort study. METHODS: Through retrospective analysis of Midwestern U.S. electronic health records, diagnoses, prescriptions, and natural language processing identified CC - at least three medical encounters with cough, with 56-120 days between first and last encounter - and a 'non-chronic cohort'. Student's t-test, Pearson's chi-square, and zero-inflated Poisson models were used. RESULTS: About 20% of 23,210 patients with CC were prescribed OCCS; odds of an OCCS prescription were twice as great in CC. In CC, OCCS drugs were ordered in 38% with Medicaid insurance and 15% with commercial insurance. CONCLUSION: Findings identify an important role for opioids in CC, and opportunity to learn more about the drugs' effectiveness.

Human placental organoids as a model to probe early gestation maternal immune dynamics.

During pregnancy, the human placenta establishes tolerance toward fetal allogeneic tissue, where specialized trophoblast subtypes play a complex role in local and peripheral immunomodulation. However, due to inadequate models to study the early gestation of the human placenta, each trophoblast subtype's role in modulating the maternal immune response has remained elusive. Here, we derived human placental organoids from early gestation trophoblast stem cells to (1) identify patterns of immunomodulatory protein expression by trophoblast subtype and (2) evaluate the effects of the placental organoid secretome on immune cell activation and regulation. We show that the three primary trophoblast phenotypes had distinct influences on immune cell phenotype and activation and that three-dimensional culture significantly alters trophoblast immunomodulation relative to traditional two-dimensional trophoblast culture.

Engineered 3D Hydrogel Matrices to Modulate Trophoblast Stem Cell-Derived Placental Organoid Phenotype.

Placental organoid models are a promising platform to study human placental development and function. Organoid systems typically use naturally derived hydrogel extracellular matrices (ECM), resulting in batch-to-batch variability that limits experimental reproducibility. As an alternative, synthetic ECM-mimicking hydrogel matrices offer greater consistency and control over environmental cues. Here, we generated trophoblast stem cell-derived placental organoids using poly(ethylene glycol) (PEG) hydrogels with tunable degradability and placenta-derived ECM cues to evaluate trophoblast differentiation relative to Matrigel and two-dimensional (2D) culture controls. Our data demonstrate that PEG hydrogels support trophoblast viability and metabolic function comparable to gold standard Matrigel. Additionally, phenotypic characterization via proteomic analysis revealed that PEG and Matrigel matrices drive syncytiotrophoblast and extravillous trophoblast-dominant placental organoid phenotypes, respectively. Further, three-dimensional (3D) environments promoted greater integrin expression and ECM production than 2D culture. This study demonstrates that engineered 3D culture environments can be used to reliably generate placental organoids and guide trophoblast differentiation.

Understanding healthcare providers' preferred attributes of pediatric pneumococcal conjugate vaccines in the United States.

As higher-valent pneumococcal conjugate vaccines (PCVs) become available for pediatric populations in the US, it is important to understand healthcare provider (HCP) preferences for and acceptability of PCVs. US HCPs (pediatricians, family medicine physicians and advanced practitioners) completed an online, cross-sectional survey between March and April 2023. HCPs were eligible if they recommended or prescribed vaccines to children age <24 months, spent ≥25% of their time in direct patient care, and had ≥2 y of experience in their profession. The survey included a discrete choice experiment (DCE) in which HCPs selected preferred options from different hypothetical vaccine profiles with systematic variation in the levels of five attributes. Relative attribute importance was quantified. Among 548 HCP respondents, the median age was 43.2 y, and the majority were male (57.9%) and practiced in urban areas (69.7%). DCE results showed that attributes with the greatest impact on HCP decision-making were 1) immune response for the shared serotypes covered by PCV13 (31.4%), 2) percent of invasive pneumococcal disease (IPD) covered by vaccine serotypes (21.3%), 3) acute otitis media (AOM) label indication (20.3%), 4) effectiveness against serotype 3 (17.6%), and 5) number of serotypes in the vaccine (9.5%). Among US HCPs, the most important attribute of PCVs was comparability of immune response for PCV13 shared serotypes, while the number of serotypes was least important. Findings suggest new PCVs eliciting high immune responses for serotypes that contribute substantially to IPD burden and maintaining immunogenicity against serotypes in existing PCVs are preferred by HCPs.

Incidence of pneumococcal disease in children ≤48 months old in the United States: 1998-2019.

BACKGROUND: Pneumococcal disease (PD) is a major cause of morbidity and mortality among children, particularly in the youngest age groups. This study aimed to assess the incidence of PD over time by age group in young children with commercial or Medicaid coverage in the US. METHODS: Episodes of invasive pneumococcal disease (IPD), all-cause pneumonia (ACP), and acute otitis media (AOM) were identified in the MarketScan® Commercial and Medicaid claims databases using diagnosis codes among children aged ≤ 48 months with confirmed date of birth (DoB), at any time during the study period (1998-2019). DoB was assigned using diagnosis codes for birth or delivery using the child's or mother's medical claims to ensure accurate age determination. Annual incidence rates (IRs) were calculated as number of disease episodes/100,000 person-years (PY) for IPD and ACP and episodes/1,000 PY for AOM, for children aged 0-6, 7-12, 12-24, and 25-48 months. RESULTS: Annual IPD IRs declined from 53 to 7 episodes/100,000 PY between 1998 and 2019 in commercially-insured and 58 to 9 episodes/100,000 PY between 2001 and 2019 in Medicaid-insured children. Annual ACP IRs declined from 5,600 to 3,952 episodes/100,000 PY, and from 6,706 to 4,521 episodes/100,000 PY, respectively, over these periods. In both populations, children aged 0-6 months had the highest incidence of IPD and inpatient ACP. Annual AOM IRs declined from 1,177 to 738 episodes/1,000 PY (commercially-insured) and 633 to 624 episodes/1,000 PY (Medicaid-insured), over these periods. IRs were higher in rural vs. urban areas for all disease manifestations. CONCLUSIONS: Incidence rates of IPD, ACP, and AOM decreased in children with commercial insurance and Medicaid coverage from 1998 to 2019. However, burden of disease remained substantial, with higher annual IRs for IPD and ACP for Medicaid-insured vs. commercially-insured children. IPD and inpatient ACP were most common in the youngest children 0-6 months old, followed by the 7-12-month age group.

Potential serotype-specific effectiveness against IPD of pneumococcal conjugate vaccines V114 and PCV20 in children given a 2+1 dosing regimen.

BACKGROUND: Next generation, higher valency pneumococcal conjugate vaccines (PCVs) are assessed and licensed by comparing the immune response across serotypes shared with the PCVs that are standard of care for prevention of pneumococcal disease. METHODS: Using a previously qualified method we predicted the serotype-specific vaccine effectiveness (VE) against invasive pneumococcal disease of V114 and PCV20 for the serotypes shared with PCV13 in an EU, Russian, and Australian pediatric population that is recommended to receive a 2 + 1 dosing regimen. RESULTS: The estimated protective antibody concentrations ranged from 0.03 (serotype 23F) to 1.49 µg/mL (serotype 19F). Predicted VE values for V114 ranged from 79% (serotype 5) to 100% (serotype 23F). V114 had comparable effectiveness to PCV13 for all but one of shared serotypes, with predicted higher effectiveness (in V114) against serotype 3 (93% vs. 65%). Predicted VE values for PCV20 ranged from 47% (serotype 3) to 91% (serotype 14). PCV20 predicted VE was lower than PCV13's for serotypes 4, 19F, 23F, 1, 3, 5, 6A, 7F, and 19A. CONCLUSIONS: Predicted serotype-specific VE values suggest that, with a 2 + 1 dosing regimen, V114 will have greater effectiveness than PCV20 against PCV13 serotypes, particularly for the still-prevalent serotype 3. Real-world VE studies will ultimately provide clarity on the effectiveness of novel PCVs and support further confidence in and/or improvements to modeling efforts.

Pediatric pneumococcal conjugate vaccines (PCVs) were first introduced in Europe in the early 2000s and their incorporation into national immunization programs has helped decrease the incidence of invasive pneumococcal disease (IPD) in Europe and globally. However, some IPD persists, due both to the emergence of non-vaccine pneumococcal serotypes and to the persistence of certain vaccine-targeted serotypes. Higher valency vaccines have been developed to help prevent IPD arising from these serotypes. The goal of the present study is to employ a previously developed model to predict the serotype-specific vaccine effectiveness of higher valency PCVs in a pediatric population that is recommended to receive a 2 + 1 dosing schedule.

A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

pO2 reporter composite hydrogel macroencapsulation devices for magnetic resonance imaging oxygen quantification.

Hydrogel cell encapsulation devices are a common approach to reduce the need for chronic systemic immunosuppression in allogeneic cell product transplantation. Macroencapsulation approaches are an appealing strategy, as they maximize graft retrievability and cell dosage within a single device; however, macroencapsulation devices face oxygen transport challenges as geometries increase from preclinical to clinical scales. Device design guided by computational approaches can facilitate graft oxygen availability to encapsulated cells in vivo but is limited without accurate measurement of oxygen levels within the transplant site and graft. In this study, we engineer pO2 reporter composite hydrogels (PORCH) to enable spatiotemporal measurement of oxygen tension within macroencapsulation devices using the proton Imaging of siloxanes to map tissue oxygenation levels (PISTOL) magnetic resonance imaging approach. We engineer two methods of incorporating siloxane oximetry reporters within hydrogel devices, an emulsion and microbead-based approach, and evaluate PORCH cytotoxicity on co-encapsulated cells and accuracy in quantifying oxygen tension in vitro. We find that both emulsion and microbead PORCH approaches enable accurate in situ oxygen quantification using PISTOL magnetic resonance oximetry, and that the emulsion-based PORCH approach results in higher spatial resolution.

Characterization of diseased primary human hepatocytes in an all-human cell-based triculture system.

Liver diseases, including NAFLD, are a growing worldwide health concern. Currently, there is a lack of suitable in vitro models that sustain basic primary human hepatocyte (PHH) morphology and functionality while supporting presentation of disease-associated phenotypic characteristics such as lipid accumulation and inflammasome activation. In TruVivo, an all-human triculture system (hTCS), basic metabolic functions were characterized in PHHs isolated from normal or diseased livers during two-weeks of culture. Decreases in albumin and urea levels and CYP3A4 activity were seen in diseased-origin PHHs compared to normal PHHs along with higher CYP2E1 expression. Positive expression of the macrophage markers CD68 and CD163 were seen in the diseased PHH preparations. Elevated levels of the pro-inflammatory cytokines IL-6 and MCP-1 and the fibrotic markers CK-18 and TGF-ß were also measured. Gene expression of FASN, PCK1, and G6PC in the diseased PHHs was decreased compared to the normal PHHs. Further characterization revealed differences in lipogenesis and accumulation of intracellular lipids in normal and diseased PHHs when cultured with oleic acid and high glucose. TruVivo represents a promising new platform to study lipogenic mechanisms in normal and diseased populations due to the preservation of phenotypic differences over a prolonged culture period.

Controlling placental spheroid growth and phenotype using engineered synthetic hydrogel matrices.

The human placenta is a complex organ comprised of multiple trophoblast subtypes, and inadequate models to study the human placenta in vitro limit the current understanding of human placental behavior and development. Common in vitro placental models rely on two-dimensional culture of cell lines and primary cells, which do not replicate the native tissue microenvironment, or poorly defined three-dimensional hydrogel matrices such as Matrigel™ that provide limited environmental control and suffer from high batch-to-batch variability. Here, we employ a highly defined, synthetic poly(ethylene glycol)-based hydrogel system with tunable degradability and presentation of extracellular matrix-derived adhesive ligands native to the placenta microenvironment to generate placental spheroids. We evaluate the capacity of a hydrogel library to support the viability, function, and phenotypic protein expression of three human trophoblast cell lines modeling varied trophoblast phenotypes and find that degradable synthetic hydrogels support the greatest degree of placental spheroid viability, proliferation, and function relative to standard Matrigel controls. Finally, we show that trophoblast culture conditions modulate cell functional phenotype as measured by proteomics analysis and functional secretion assays. Engineering precise control of placental spheroid development in vitro may provide an important new tool for the study of early placental behavior and development.

A heterogenous population of extracellular vesicles mobilize to the alveoli postinjury.

BACKGROUND: Acute lung injury and subsequent resolution following severe injury are coordinated by a complex lung microenvironment that includes extracellular vesicles (EVs). We hypothesized that there is a heterogenous population of EVs recruited to the alveoli postinjury and that we could identify specific immune-relevant mediators expressed on bronchoalveolar lavage (BAL) EVs as candidate biomarkers of injury and injury resolution. METHODS: Mice underwent 30% TBSA burn injury and BAL fluid was collected 4 hours postinjury and compared with sham. Extracellular vesicles were purified and single vesicle flow cytometry (vFC) was performed using fluorescent antibodies to quantify the expression of specific cell surface markers on individual EVs. Next, we evaluated human BAL specimens from injured patients to establish translational relevance of the mouse vFC analysis. Human BAL was collected from intubated patients following trauma or burn injury, EVs were purified, then subjected to vFC analysis. RESULTS: A diverse population of EVs were mobilized to the alveoli after burn injury in mice. Quantitative BAL vFC identified significant increases in macrophage-derived CD44+ EVs (preinjury, 10.8% vs. postinjury, 13%; p < 0.05) and decreases in IL-6 receptor alpha (CD126) EVs (preinjury, 19.3% vs. postinjury, 9.3%, p < 0.05). Bronchoalveolar lavage from injured patients also contained a heterogeneous population of EVs derived from myeloid cells, endothelium, and epithelium sources, with CD44+ EVs being highly detected. CONCLUSION: Injury causes mobilization of a heterogeneous population of EVs to the alveoli in both animal models and injured patients. Defining EV release after injury will be critical in identifying diagnostic and therapeutic targets to limit postinjury acute lung injury.

Predicted serotype-specific effectiveness of pneumococcal conjugate vaccines V114 and PCV20 against invasive pneumococcal disease in children.

BACKGROUND: Next-generation, higher-valency pneumococcal conjugate vaccines (PCVs), 15-valent PCV V114 and 20-valent PCV (PCV20), have been assessed by comparing their immune responses across serotypes shared with the 13-valent PCV (PCV13). Without efficacy or real-world vaccine effectiveness (VE) it becomes important to relate IgG titers to VE to aid in the interpretation of the immune response elicited by V114 and PCV20. METHODS: We estimated the protective antibody concentrations for each serotype in 7-valent PCV (PCV7) and PCV13 which were then used to predict the serotype-specific VE for each PCV7 and PCV13 non PCV7 serotype present in V114 and PCV20. RESULTS: The predicted effectiveness of V114 was comparable to PCV7 and PCV13 for 11 of the 13 shared serotypes (1, 4, 5, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F), with improved effectiveness against serotype 3 and decreased effectiveness against serotype 6A. PCV20 had predicted effectiveness comparable to PCV7 and PCV13 for 7 of the 13 shared serotypes (5, 6A, 7F, 9 V, 18C, 19F, and 23F), with decreased effectiveness against the remaining serotypes (1, 3, 4, 6B, 14, and 19A). CONCLUSIONS: Prediction of serotype-specific VE values suggests that V114 retains greater effectiveness than PCV20 toward most serotypes present in PCV7 and PCV13.

Pediatric pneumococcal conjugate vaccines (PCVs) first became available in 2000, when the seven-valent PCV (PCV7) was approved. Since then, PCV7 has been replaced by higher-valency vaccines, including the ten-valent (PCV10) and thirteen-valent (PCV13) vaccines and, more recently, fifteen- and twenty-valent vaccines (V114 and PCV20, respectively). The increase in valency provides broader serotype coverage against invasive pneumococcal disease (IPD) in children. However, IPD due to serotypes contained in PCV7 and PCV13 continue to be observed. In the current study, we used a previously published method to estimate the vaccine effectiveness of V114 and PCV20 in a US and Puerto Rican pediatric population that is recommended to receive a 3 + 1 dosing schedule.

Translation of cell therapies to treat autoimmune disorders.

Autoimmune diseases are a diverse and complex set of chronic disorders with a substantial impact on patient quality of life and a significant global healthcare burden. Current approaches to autoimmune disease treatment comprise broadly acting immunosuppressive drugs that lack disease specificity, possess limited efficacy, and confer undesirable side effects. Additionally, there are limited treatments available to restore organs and tissues damaged during the course of autoimmune disease progression. Cell therapies are an emergent area of therapeutics with the potential to address both autoimmune disease immune dysfunction as well as autoimmune disease-damaged tissue and organ systems. In this review, we discuss the pathogenesis of common autoimmune disorders and the state-of-the-art in cell therapy approaches to (1) regenerate or replace autoimmune disease-damaged tissue and (2) eliminate pathological immune responses in autoimmunity. Finally, we discuss critical considerations for the translation of cell products to the clinic.

Pneumococcal Vaccine Breakthrough and Failure in Infants and Children: A Narrative Review.

Globally, Streptococcus pneumoniae is a leading cause of vaccine-preventable morbidity and mortality in infants and children. In recent decades, large-scale pediatric immunization programs have substantially reduced the incidence of invasive pneumococcal disease. Despite this, residual vaccine-type pneumococcal disease remains in the form of vaccine breakthrough and vaccine failure. This targeted literature review aims to discuss aspects of vaccine breakthrough and failure in infants and children, including disease epidemiology, clinical presentation, risk factors, vaccination schedules, vaccine serotypes, correlates of protection, comorbidities, disease surveillance, and potential implications for future vaccine development.

An All-Human Hepatic Culture System for Drug Development Applications.

Finding a long-term, human-relevant culture model for primary human hepatocytes (PHHs) for pharmacological and toxicological studies remains a challenge. Current in vitro model platforms are often inconvenient and complex, lack phenotypic stability over time, and do not support multiple PHH lots, lacking experimental reproducibility and flexibility. Here, we provide a detailed protocol for the thawing, plating, and maintenance of an all-human 2D+ hepatic system (TV2D+), which takes advantage of standard two-dimensional (2D) culture techniques and equipment while maintaining the longevity and phenotypic stability over time that typically accompany more complex three-dimensional (3D) systems. The results show attachment and percent plateability in TV2D+ as a function of PHH seeding density, as well as stable functionality for at least 2 weeks in culture. A range of PHH seeding densities are assessed to achieve a successful long-term culture. When established properly, the PHHs in TV2D+ organize into hepatocyte colonies, express a hepatic-specific marker, and maintain viability, architectural integrity, and physiologically relevant levels of albumin and urea. This unique combination of attributes makes the TV2D+ system a suitable hepatic model for a variety of pharmacological and toxicological applications.

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPß pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

An indirect treatment comparison (ITC) and matching-adjusted indirect comparison (MAIC) between a 15-valent (V114) and a 20-valent (PCV20) pneumococcal conjugate vaccine among healthy infants.

OBJECTIVES: Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. METHODS: Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12-15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant's age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. RESULTS: V114 was non-inferior (marginRRD>-10%-point; marginGMCratio >0.5) to PCV20 (p-value <0.001) for all endpoints. V114 was superior (marginRRD >0%-point; marginGMCratio >1.2) to PCV20 (p-value <0.001) for serotype 3: RRD was 34.5% (95%CI 27.9%-41.1%) PD3, and IgG GMC ratios were 2.39 (95%CI 2.12-2.68) PD3 and 2.15 (95%CI 1.90-2.41) PD4. CONCLUSION: Immune response to V114 administered in a 3 + 1 schedule in healthy infants was considered non-inferior to PCV20 for all 13 PCV13 serotypes and superior for serotype 3 PD3 and PD4. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers NCT03893448, NCT04382326.

Engineering of Trophoblast Extracellular Vesicle-Delivering Hydrogels for Localized Tolerance Induction in Cell Transplantation.

Purpose: The need for chronic systemic immunosuppression, which presents a host of acute risks to transplantation patients, remains the primary limitation for the translation of many cell therapies, such as insulin secreting cells for the treatment of type 1 diabetes. Trophoblasts are the professional tolerogenic cells of the placenta, and they secrete a range of soluble factors to induce antigen specific tolerance toward allogeneic fetal tissue during pregnancy, including extracellular vesicles. Here we develop a trophoblast extracellular vesicle-delivering hydrogel designed for sustained, localized tolerogenic factor delivery within a transplant site to induce localized tolerance toward cell grafts. Methods: We engineer a synthetic poly(ethylene glycol)-based hydrogel system to tether extracellular vesicles for sustained delivery, and compare this system to passive vesicle entrapment within an alginate hydrogel system. We characterize trophoblast extracellular vesicles for size and morphology, and evaluate vesicle tolerogenic protein content via proteomic analysis. We validate the retention and tethering of extracellular vesicles within the hydrogel systems via scanning electron and stimulated emission depletion microscopy, and measure vesicle release rate over time. Finally, we evaluate trophoblast extracellular vesicle influence on natural killer cell activation in vitro. Results: We isolated trophoblast extracellular vesicles and proteomics confirmed the presence of tolerogenic factors. We confirmed the presence of extracellular vesicles within hydrogel delivery vehicles, and synthetic hydrogels extended extracellular vesicle release relative to a passive hydrogel system. Finally, extracellular vesicles reduced natural killer cell activation in vitro, confirming the tolerogenic potential of hydrogel-delivered extracellular vesicles. Conclusions: This tolerogenic extracellular vesicle-delivering hydrogel platform designed for delivery within a transplant site could serve as an alternative to systemic immunosuppression in cell transplantation, potentially reducing the risks associated with cell therapies and widening the eligible patient population.

Cost-effectiveness analysis of pediatric immunization program with 15-valent pneumococcal conjugate vaccine in Japan.

BACKGROUND: The 15-valent pneumococcal conjugate vaccine (PCV15 or V114) has recently been approved for pediatric vaccination against pneumococcal diseases (PDs) in Japan. The study aims to evaluate the cost-effectiveness of pediatric vaccination with V114 versus 13-valent PCV (PCV13) in Japan. METHODS: The study used a decision analytical Markov model to estimate the cost and effectiveness outcomes for a birth cohort in Japan over a 10-year time horizon. The model tracked the occurrences of acute PD events, including invasive PD (IPD), non-bacteremic pneumococcal pneumonia (NBPP) and pneumococcal acute otitis media (AOM) and the long-term impact of post-meningitis sequalae. Vaccine effectiveness was estimated based on literature and assumptions, and accounted for indirect effects and vaccine waning. The base case took the societal perspective, including both direct and indirect costs, while a healthcare payer perspective was modeled in a scenario analysis. Additional scenario analyses and sensitivity analyses were conducted. RESULTS: In the base case, V114 was associated with an incremental gain of 24 quality-adjusted life years and a reduction of ¥365,610,955 in total costs compared to PCV13. It was expected to reduce the number of pneumococcal AOM, NBPP, and IPD cases by 1,832, 1,333 and 25, respectively. All scenario analyses and most sensitivity analyses showed that V114 was a dominant strategy compared to PCV13. CONCLUSIONS: Pediatric vaccination with V114 is expected to lead to cost savings and more health benefits compared to PCV13 in Japan from both societal and healthcare payer perspectives. The findings are robust under plausible assumptions and inputs.