Delivery Strategies Research Articles

Current Formulation Strategies to Design Novel Carriers for Targeted Drug Delivery and Management of Infectious Keratitis: A Comprehensive Review on the Present State of the Art

Objective: Infectious keratitis is a pernicious disease that affects the anterior segment of the eye and is one the leading causes of blindness worldwide. This disease may cause severe visual impairment or permanent vision damage if left untreated. Discussion: No doubt there are many conventional drug delivery systems to treat ocular keratitis, yet it is the fifth leading cause of blindness globally. This is the result of the eye's complex anatomy and barrier system, which restricts the total ocular contact time of the conventional formulations resulting in underdosing. The widely used traditional formulations to treat keratitis, like antibiotic eye drops and ointments, are rendered useless due to less ocular contact time and low therapeutic drug levels at the target ocular site. The main requirement of the present time is to develop novel drug delivery-backed stratagems to overcome the shortcomings of conventional formulations, which will reduce the morbidity associated with infectious keratitis and improve clinical outcomes. It is worth mentioning that there are documented incidents of Herpetic keratitis of the cornea followed by COVID-19 infection and vaccination. Conclusion: This paper is a rigorous review of all the novel drug delivery strategies to combat ocular keratitis. These future drug delivery strategies will pave the way for the present time researcher and formulation chemists to develop multi-dimensional novel formulations that are safe, patient-compliant, and surpass the ocular barriers to maintain therapeutic drug levels in ocular tissues.

Stochastic Processes in the Analysis of Electrical Load Forecasting

It is exceptionally vital to be able to precisely foresee power loads since that's a key portion of overseeing vitality well and building framework. The reason of this consider is to see into how irregular forms can be utilized, particularly in analyzing and anticipating changes in power stack designs over a run of time scales. Since power stack request changes over time, we require precise arranging strategies that can take into consideration the questions and complicated connections. The primary portion of the think about looks at well-known stochastic forms like autoregressive coordinates moving normal (ARIMA), Gaussian forms, and Markov models to see how well they can depict the irregular viewpoints of power stack information. It is checked to see how well each demonstrate can handle distinctive sorts of changes in time and whether it can be utilized in large-scale computing apps. The ponder too looks at how machine learning strategies can be combined with irregular forms to form estimates more precise. Profound learning and outfit strategies are tried to see in the event that they can learn complex designs and nonlinear connections from past stack information, which would make them valuable in expansion to irregular modeling strategies. A comparison of these strategies appears their aces and cons in terms of how well they make expectations, how quickly they work, and how well they hold up against demonstrate presumptions. The think about too talks approximately how imperative show determination components are for judging foreseeing victory. These incorporate demonstrate assessment strategies and measures like cruel outright rate mistake (MAPE) and root cruel square mistake (RMSE). It is talked around what precise stack estimating implies in genuine life, such as how to move forward vitality generation and delivery strategies, keep the lattice steady, and make beyond any doubt that assets are utilized proficiently.

Leukemia Cell Hitchhiking Hypoxia Responsive Nanogel for Improved Immunotherapy of Acute Myeloid Leukemia

AbstractImmune checkpoint blockade (ICB) with anti‐CD47 antibodies (aCD47) is a promising therapeutic approach that has the potential to revolutionize the treatment of acute myeloid leukemia (AML). However, the low immune response rate and high systemic hematotoxicity remain substantial barriers to its success in clinical AML treatment. A synthetic protein nanogel formulation of aCD47 and resiquimod (R848) (termed CR‐TNG) is developed that targets TIM‐3 on the surface of leukemia cells. Upon intravenous injection, the CR‐TNG efficiently conjugates onto the blood‐circulating leukemia cells and migrates toward the bone marrow (BM) by exploiting the natural BM homing capability of leukemia cells. CR‐TNG releases aCD47 and R848 in a bone marrow hypoxic microenvironment, which significantly induces immunosuppression and enhances the anti‐leukemia immune response by activating macrophage “eat me” signaling and priming myeloid macrophages in the BM niche. These findings provide a leukemia cell‐hitchhiking drug delivery strategy that addresses both systemic hematotoxicity and low immune response rate in AML.

Polypropylene sulfide methotrexate nanoparticles target the synovial lymphatic system to restore immune tolerance in rheumatoid arthritis

Around 40 % of patients fail to achieve primary clinical outcomes for rheumatoid arthritis (RA). The growth of lymphatic system in the synovial membrane, is a primary response during RA inflammation. It is suggested that a delivery strategy targeting immunosuppressive agents to the synovial lymph nodes and then to the immune cells is beneficial for resolving arthritis. This study introduced a synthetic polypropylene sulfide methotrexate nano-delivery system (PPS-MTX), which was prepared by covalently bonding methotrexate to polypropylene sulfide, with a diameter size range of 36 nm. It enhanced joint accumulation and retention, which can be selectively uptake by antigen-presenting cells in the synovial lymphatic system. The results indicated that PPS-MTX nanoparticles effectively improved arthritis disease progression and restored the immune tolerance microenvironment in the synovial lymphatic system, promoting peripheral tolerance in collagen-induced arthritis mice. Additionally, no systemic toxicity was observed. This study presents a promising targeted strategy for inducing immune tolerance in the treatment of rheumatoid arthritis.

Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (Cmax = 287.39 ± 106.82 ng/mL) and EMNs (Cmax = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.

Peptide-functionalized gold nanoparticles for boron neutron capture therapy with the potential to use in Glioblastoma treatment

Glioblastoma is a highly aggressive glioma with limited treatment options. Boron neutron capture therapy (BNCT) offers a promising approach for refractory cancers, utilizing boron-10 (10B) and thermal neutrons to generate cytotoxic particles. Effective BNCT depends on selective targeting and retention of 10B in tumors. Current BNCT drugs face issues with rapid clearance and poor tumor accumulation. To address this, we developed gold nanoparticles (AuNPs) functionalized with cyclic arginine-glycine-aspartic acid (cRGD) peptides as a nanocarrier for Sodium Mercaptododecaborate (BSH), resulting in AuNPs-BSH&PEG-cRGD. In vitro, AuNPs-BSH&PEG-cRGD increased 10B content in GL261 glioma cells by approximately 2.5-fold compared to unmodified AuNPs-BSH&PEG, indicating enhanced targeting due to cRGD's affinity for integrin receptor αvβ3. In a subcutaneous glioma mouse model, 6 h post-intratumoral administration, the 10B concentration in tumors was 17.98 μg/g for AuNPs-BSH&PEG-cRGD, significantly higher than 0.45 μg/g for BSH. The tumor-to-blood (T/B) and tumor-to-normal tissue (T/N) ratios were also higher for AuNPs-BSH&PEG-cRGD, suggesting improved targeting and retention. This indicates that AuNPs-BSH&PEG-cRGD may enhance BNCT efficacy and minimize normal tissue toxicity. In summary, this study provides a novel strategy for BSH delivery and may broaden the design vision of BNCT nano-boron capture agents.

Ex Vivo Machine Perfusion as a Platform for Lentiviral Gene Delivery in Rat Livers.

Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors carrying biosensor constructs with Gaussia Luciferase (GLuc) were introduced to rodent livers during a 72-hour perfusion period, with a targeted delivery of 3 × 107 infection units (IU). Following the initial 24-hour exposure required for viral transduction, an additional 48 hours was necessary to observe gene expression, analogous to in vitro benchmarks. The perfused livers displayed significantly increased luminescence compared to controls, illustrating successful genetic modification. These findings validate the ex vivo use of lentiviral particles in a rodent liver model and lay the groundwork for a broad range of applications through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical transplantation.

Device-based 24-hour movement behaviours in adult phase III cardiac rehabilitation service-users during the COVID-19 pandemic: a mixed-methods prospective observational study

Purpose To examine changes in device-based 24-hour movement behaviours (MB), and facilitators and barriers to physical activity (PA) and exercise, during remotely-delivered cardiac rehabilitation (RDCR). Materials and methods This prospective observational study used wrist-worn GENEActiv accelerometers to assess MB of 10 service-users (63 ± 10 years) at the start, middle, and end of three-months of RDCR. Barriers and facilitators to PA and exercise were explored through self-report diaries and analysed using content analysis. Results At start, service-users were sedentary for 12.6 ± 0.7 h · day−1 and accumulated most PA at a light-intensity (133.52 ± 28.57 min · day−1) – neither changed significantly during RDCR. Sleep efficiency significantly reduced from start (88.80 ± 4.2%) to the end (86.1 ± 4.76%) of CR, with values meeting health-based recommendations (≥85%). Barriers to RDCR exercise included exertional discomfort and cardiac symptoms, and reduced confidence when exercising alone. Setting meaningful PA goals, self-monitoring health targets, and having social support, facilitated PA and exercise during RDCR. Conclusions Our RDCR programme failed to elicit significant changes in MB or sleep. To increase the likelihood of successful RDCR, it is important to promote a variety of exercise and PA options, target sedentary time, and apply theory to RDCR design, delivery, and support strategies.

Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy.

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8+ T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8+ T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8+ T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8+ T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8+ T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8+ T cells, which may present a promising strategy for brain-tumor immunotherapy.

Oral cholera vaccine coverage in Goma, Democratic Republic of the Congo, 2022, following 2019–2020 targeted preventative mass campaigns

BackgroundIn 2019–2020, preventative Oral Cholera Vaccine campaigns were conducted in 24/32 non-contiguous health areas of Goma, DR Congo. In August 2022, we measured coverage and factors potentially influencing success of the delivery strategy. MethodsWe used random geo-sampled stratified cluster survey to estimate OCV coverage and assess population movement, diarrhea history, and reasons for non-vaccination. Results603 households were visited. Coverage with at least one dose was 46.4 % (95 %CI: 41.8–51.0), and 50.1 % (95 %CI: 45.4–54.8) in areas targeted by vaccination compared to 26.3 % (95 %CI: 19.2–34.9) in non-targeted areas. Additionally, 7.0 % of participants reported moving from outside Goma since 2019, and 5.4 % reported history of severe diarrhea. Absence and unawareness were the main reasons for non-vaccination. ConclusionResults suggest that targeting non-contiguous urban areas had a coverage-diluting effect. Targeting entire geographically contiguous areas, adapted distribution, and regular catch-up campaigns are operational recommendations to reach higher coverages arising from the study.

PEI-Engineered Lipid@PLGA Hybrid Nanoparticles for Multimodal Delivery of Antigens and Immune Adjuvants to the Respiratory Mucosa.

Antigen delivery via respiratory mucosal surfaces is an interesting needle-free option for vaccination. Nonetheless, it demands for the design of especially tailored formulations. Here, lipid/poly(lactic-co-glycolic) acid (PLGA) hybrid nanoparticles (hNPs) for the combined delivery of an antigen, ovalbumin (Ova), and an adjuvant, synthetic unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG) motifs, is developed. A panel of Ova/CpG-loaded lipid@PLGA hNPs with tunable size and surface is attained by exploiting two lipid moieties, 1,2 distearoil-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) and monophosphoryl lipid A (MPLA), with or without polyethyleneimine (PEI). It is gained insights on the lipid@PLGA hNPs through a combination of techniques to analytically determine the specific moiety on the surface, the spatial distribution of the components and the internal structure of the nanoplatforms. The collected results suggest that PEI plays a role of paramount importance not only in promoting in vitro antigen escape from lysosomes and enhancing antigen cross-presentation, but also in determining the arrangement of the moieties in the final architecture of the hNPs. Though multicomponent PEI-engineered lipid@PLGA hNPs turn out as a viable strategy for delivery of antigens and adjuvant to the respiratory mucosa, tunable nanoparticle features are achievable only through the optimal selection of the components and their relative amounts.

Revealing the pH-dependent conformational changes in sol g 2.1 protein and potential ligands binding

Sol g 2, a major protein found in the venom of the tropical fire ant (Solenopsis geminata), is well-known for its ability to bind various hydrophobic molecules. In this study, we investigate the binding activity of recombinant Sol g 2.1 protein (rSol g 2.1) with potential molecules, including (E)-β-Farnesene, α-Caryophyllene, and 1-Octen-3-ol at different pH levels (pH 7.4 and 5.5) using fluorescence competitive binding assays (FCBA). Our results revealed that Sol g 2.1 protein has higher affinity binding with these ligands at neutral pH. Relevance to molecular docking and molecular dynamics simulations were utilized to provide insights into the stability and conformational dynamics of Sol g 2.1 and its ligand complexes. After simulation, we found that Sol g 2.1 protein has higher affinity binding with these ligands as well as high structural stability at pH 7.4 than at an acidic pH level, indicating by RMSD, RMSF, Rg, SASA, and principal component analysis (PCA). Additionally, the Sol g 2.1 protein complexes at pH 7.4 showed significantly lower binding free energy (∆Gbind) and higher total residue contributions, particularly from key non-polar amino acids such as Trp36, Met40, Cys62, and Ile104, compared to the lower pH environment. These explain why they exhibited higher binding affinity than the lower pH. Therefore, we suggested that Sol g 2.1 protein is a pH-responsive carrier protein. These findings also expand our understanding of protein–ligand interactions and offer potential avenues for the development of innovative drug delivery strategies targeting Sol g 2.1 protein.

Dual-Prodrug-Based Hyaluronic Acid Nanoplatform Provides Cascade-Boosted Drug Delivery for Oxidative Stress-Enhanced Chemotherapy.

Insufficient drug accumulation in tumors severely limits the antitumor efficiency of hyaluronic acid (HA) nanomedicine in solid tumors due to superficial penetration depth, low cell uptake, and nonspecific drug release. Hence, we constructed a dual NO prodrug (alkynyl-JSK) and doxorubicin prodrug (cis-DOX)-conjugated HA nanoparticle (HA-DOX-JSK NPs), which achieved cascade-boosted drug delivery efficiency based on a relay strategy of NO-mediated deep tumor penetration─HA target CD44 tumor cell uptake─tumor microenvironment (TME)-responsive drug release. The nanoparticle demonstrated sustained and locoregionally GSH/GST-triggered NO release and GSH/pH-responsive DOX release in the tumor. The released NO first mediated collagen degradation, causing deep tumor penetration of nanoparticles in the dense extracellular matrix. Immediately, HA was relayed to enhance CD44-targeted tumor cell uptake, and then, the nanoparticles were finally triggered by specific TME to release DOX and NO in the deep tumor. Relying on the relayed delivery strategy, a significant improvement of DOX accumulation in tumors was realized. Moreover, NO depleted GSH-induced intracellular reactive oxygen species, enhancing DOX chemotherapy. Based on this strategy, the tumor inhibition rate in breast cancer was up to 87.8% in vivo. The relay drug-delivery HA system would greatly cascade-boost drug accumulation in deep tumors for efficient solid tumor therapy.

COVID-19 vaccine uptake in a predominantly minoritized cohort hospitalized during the early pandemic in New York City

BackgroundMinoritized communities in the United States have had higher COVID-19 mortality and lower vaccine uptake. The influence of previous SARS-CoV-2 infection, initial disease severity, and persistent symptoms on COVID-19 vaccine uptake in Black and Latinx communities has not been examined. ObjectiveTo investigate whether initial COVID-19 severity, persistent symptoms, and other correlates affected vaccine uptake in a predominantly minoritized cohort hospitalized for COVID-19 during the early pandemic in New York City. DesignIn this historical cohort study, we abstracted electronic health record data on demographics, comorbidities, hospital oxygen requirements, symptoms at 3 and 6 months post-admission, COVID-19 vaccinations through November 2022, and influenza vaccinations during the 2018–2019 through 2021–2022 seasons. Unadjusted and adjusted odds ratios were estimated through logistic regression analyses of correlates of COVID-19 vaccination, on-time vaccination, and boosting. ParticipantsSurvivors among the first 1186 adult patients hospitalized for COVID-19 between March 1 and April 8, 2020 at a large quaternary care medical center in Northern Manhattan. Main MeasuresUptake of at least one COVID-19 vaccine dose, uptake of at least one booster, and on-time vaccination. Key ResultsThe 890 surviving individuals were predominantly Latinx (54%) and Non-Hispanic Black (15%). Most had one or more comorbidities (67%), and received at least one COVID-19 vaccine dose (78%). Among those vaccinated, 57% received at least one booster, and 31% delayed vaccination. 67% experienced persistent symptoms. Multiple logistic regression showed no association between vaccine uptake and disease severity or symptom persistence. However, older age and influenza vaccination during the COVID-19 era were associated with increased vaccination, booster uptake, and on-time vaccination. ConclusionsPinpointing drivers of vaccine uptake and hesitancy is critical to increasing and sustaining COVID-19 vaccination as the field transitions to annual boosters. The association between influenza vaccination and increased vaccine uptake suggests that bundling vaccines for adults may be an effective delivery strategy.

Soccer and Vocational Training are Ineffective Delivery Strategies to Prevent HIV and Substance Abuse by Young, South African Men: A Cluster Randomized Controlled Trial.

HIV and substance abuse are common among young men, associated with a cluster of risk behaviors. Yet, most services addressing these challenges are delivered in setting underutilized by men and are often inconsistent with male identity. This cluster randomized controlled trial aimed to reduce multiple risk behaviors found among young men township areas on the outskirts of Cape Town, South Africa. Young men aged 18-29years (N = 1193) across 27 neighborhoods were randomized by area to receive HIV-related skills training during either: (1) a 12-month soccer league (SL) intervention; (2) 6-month SL followed by 6months of vocational training (VT) intervention (SL/VT, n = 9); or 3) a control condition (CC). Bayesian longitudinal mixture models were used to evaluate behaviors over time. Because we targeted multiple outcomes as our primary outcome, we analyzed if the number of significantly different outcomes between conditions exceeded chance for 13 measures over 18months (with 83%, 76%, and 61% follow-up). Only if there were three significant benefits favoring the SL/VT over the SL would benefits be significant. Outcome measures included substance use, HIV-testing, protective sexual behaviors, violence, community engagement and mental health. Consistent participation in the SL was typically around 45% over time across conditions, however, only 17% of men completed SL/VT. There were no significant differences between conditions over time based on the number of study outcomes. These structural interventions were ineffective in addressing young men's substance abuse and risk for HIV.Clinical Trial Registration: This trial was prospectively registered on 24 November 2014 with ClinicalTrials.gov (NCT02358226).

A cutting-edge new framework for the pain management in children: nanotechnology.

Pain is a subjective concept which is ever-present in the medical field. Health professionals are confronted with a variety of pain types and sources, as well as the challenge of managing a patient with acute or chronic suffering. An even bigger challenge is presented in the pediatric population, which often cannot quantify pain in a numerical scale like adults. Infants and small children especially show their discomfort through behavioral and physiological indicators, leaving the health provider with the task of rating the pain. Depending on the pathophysiology of it, pain can be classified as neuropathic or nociceptive, with the first being defined by an irregular signal processing in the nervous system and the second appearing in cases of direct tissue damage or prolonged contact with a certain stimulant. The approach is generally either pharmacological or non-pharmacological and it can vary from using NSAIDs, local anesthetics, opiates to physical and psychological routes. Unfortunately, some pathologies involve either intense or chronic pain that cannot be managed with traditional methods. Recent studies have involved nanoparticles with special characteristics such as small dimension and large surface area that can facilitate carrying treatments to tissues and even offer intrinsic analgesic properties. Pediatrics has benefited significantly from the application of nanotechnology, which has enabled the development of novel strategies for drug delivery, disease diagnosis, and tissue engineering. This narrative review aims to evaluate the role of nanotechnology in current pain therapy, with emphasis on pain in children.

Restoring vancomycin activity against resistant Enterococcus faecalis using a transcription factor decoy as a vanA operon-inhibitor.

Vancomycin-resistant enterococci (VRE) represent a public health threat due to the few available treatments. Such alarm has triggered worldwide initiatives to develop effective antimicrobial compounds and novel delivery and therapeutic strategies. vanA operon is responsible for most cases of acquired vancomycin resistance in enterococci. Development of a transcription factor decoy (TFD) system as a vanA gene transcription-inhibitor. Vancomycin MIC was determined in the presence of TFD-lipoplexes. Additionally, the effect of TFD-lipoplexes on the expression level of the vanA gene and the growth pattern of E. faecalis was evaluated. The haemolytic activity of the developed TFD-lipoplexes and their cytotoxicity were examined. TFD-lipoplexes efficiency in treating vancomycin-resistant E. faecalis (VREF) infection was tested in vivo using a systemic mice infection model. A reduction in vancomycin MIC against VRE from 256 mg/L (resistant) to 16 mg/L (intermediate susceptible), in the presence of TFD-lipoplexes, was recorded. The developed TFD-lipoplexes lacked any effect on E. faecalis growth and significantly reduced the transcription level of the vanA gene by about 3-fold. In an initial evaluation of the safety of TFD-lipoplexes, they were found not to be overtly haemolytic to human blood or cytotoxic to human skin fibroblast cells. The co-administration of TFD-lipoplexes and vancomycin efficiently eradicated VREF infection in vivo. The developed TFD-lipoplexes successfully restored vancomycin activity against VREF. They offer a safe effective unconventional therapy against this stubborn organism and present a revolution in gene therapy that can be applied to other resistance-encoding genes in various organisms.

Intranasal Delivery of circATF7IP siRNA via Lipid Nanoparticles Alleviates LPS-induced Depressive-Like Behaviors.

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

Platform‐led or seller‐led? Optimal ex ante information delivery strategy for online retail channels with product match uncertainty

Platform‐led or seller‐led? Optimal <i>ex ante</i> information delivery strategy for online retail channels with product match uncertainty

Implementing TeleSleep at Veterans Healthcare Administration: an organizational case study of adaptation and sustainment.

Veteran access to sleep medicine is of paramount importance to the Veterans Health Administration (VA). To increase access, VA has created community referral policies and programs, as well as telehealth programs. In 2017, the Office of Rural Health (ORH) funded a TeleSleep initiative focused on reaching rural Veterans with unmet sleep needs. ORH provided 3-6 years of funding to help 19 hubs support 98 spoke sites serving rural Veterans. As ORH funding concluded, each hub identified its path to sustainment. This case study follows one TeleSleep hub in VA's western geographic region as it transitioned from ORH funding sustainment as a regional Sleep Clinical Resource Hub. This case study describes the real-world process of adaptation in care delivery strategies. One key area of adaptation revolved around whether to deliver care via the patient's home facility or the provider's home facility. In early 2021, the TeleSleep team implemented an innovative provider transfer model, where temporary reinforcements from the TeleSleep hub increased the workforce capacity of spoke sites, similar to the concept of locum tenens. In this provider transfer model, TeleSleep clinicians scheduled, documented, and billed for each encounter at the Veteran's home facility. Positioning TeleSleep clinicians as local providers facilitated communication and referrals and promoted continuity and quality of care for Veterans in their home facility. This provider transfer model reduced the administrative burden of providers and schedulers and supported patient-side-only documentation of care. While this mirrors current locum tenens practice, transferring providers did not fit VA's financial model as implemented by the western region's Sleep Clinical Resource Hub. Therefore, in December 2021, VA aligned TeleSleep with VA's preferred practice of patient rather than provider transfers. In the patient transfer model, providers schedule and document in both the provider and patient electronic health records, and bill in the provider's facility. However, reflecting on this period of innovation, TeleSleep team members concluded that the provider transfer model could improve patient safety and care coordination while reducing the administrative burden of frontline clinicians. Further research and development are needed to align the provider transfer model with VA's financial model.