Subsequent Delivery Research Articles

902 Impact of method of fetal extraction in second stage cesarean delivery on subsequent preterm delivery

902 Impact of method of fetal extraction in second stage cesarean delivery on subsequent preterm delivery

Multi-Antenna Coded Caching for Location-Dependent Content Delivery

Human-computer interaction continuously evolves towards a genuinely immersive experience, submerging users in a three-dimensional (3D) virtual world. A realistic, immersive experience necessitates a highly reliable and agile wireless connection to support immense data transmission. Yet, there are abundant but underutilized memory resources available at the devices which can be harnessed as supplementary assets to reduce the excessive burden on the wireless medium. What is more, the use of Coded Caching (CC) techniques enables the cumulative cache memory of users in the network to be used as an additional communication resource. To this end, a location-dependent multi-antenna CC-based content delivery scheme tailored specifically for wireless extended reality applications is proposed in this paper. First, a novel memory allocation process is developed, enabling an appropriate trade-off between local and global caching gains. In this regard, the local caching gain is maximized when the memory is mostly dedicated to locations with poor connectivity conditions (absolute fairness). In contrast, the global caching gain is maximized when the memory is uniformly allocated among all the locations. As a result of the memory allocation process, unequal fractions of location-dependent multimedia content are cached by each user. Given the asymmetric cache placement, a novel algorithm is proposed to create suitable codewords for each user during the subsequent delivery phase, which simultaneously achieves a global and local caching gain. The proposed delivery scheme also combines global caching and spatial multiplexing gains using a weighted max-min multicast beamformer design with multi-rate modulation. Numerical experiments and mathematical analysis demonstrate significant performance gains, in terms of the 95-percentile expected delivery time, compared to unicast and multicast scenarios where either the local or global caching gain is maximized.

Triblock copolymer micelles enhance solubility, permeability and activity of a quorum sensing inhibitor against Pseudomonas aeruginosa biofilms.

Antimicrobial resistance is a threat to public health for which new treatments are urgently required. The capability of bacteria to form biofilms is of particular concern as it enables high bacterial tolerance to conventional therapies by reducing drug diffusion through the dense, exopolymeric biofilm matrix and the upregulation of antimicrobial resistance machinery. Quorum sensing (QS), a process where bacteria use diffusible chemical signals to coordinate group behaviour, has been shown to be closely interconnected with biofilm formation and bacterial virulence in many top priority pathogens including Pseudomonas aeruginosa. Inhibition of QS pathways therefore pose an attractive target for new therapeutics. We have recently reported a new series of pqs quorum sensing inhibitors (QSIs) that serve as potentiators for antibiotics in P. aeruginosa infections. The impact on biofilms of some reported QSIs was however hindered by their poor penetration through the bacterial biofilm, limiting the potential for clinical translation. In this study we developed a series of poly(β-amino ester) (PBAE) triblock copolymers and evaluated their ability to form micelles, encapsulate a QSI and enhance subsequent delivery to P. aeruginosa biofilms. We observed that the QSI could be released from polymer micelles, perturbing the pqs pathway in planktonic P. aeruginosa. In addition, one of the prepared polymer variants increased the QSIs efficacy, leading to an enhanced potentiation of ciprofloxacin (CIP) action and therefore improved reduction in biofilm viability, compared to the non-encapsulated QSI. Thus, we demonstrate QSI encapsulation in polymeric particles can enhance its efficacy through improved biofilm penetration.

56 Transperineal ultrasound-based algorithm advising women after obstetric anal sphincter injury regarding their subsequent delivery mode

56 Transperineal ultrasound-based algorithm advising women after obstetric anal sphincter injury regarding their subsequent delivery mode

Phase-Separated Lipid-Based Nanoparticles: Selective Behavior at the Nano-Bio Interface.

The membrane-protein interface on lipid-based nanoparticles influences their in vivo behavior. Better understanding may evolve current drug delivery methods toward effective targeted nanomedicine. Previously, the cell-selective accumulation of a liposome formulation in vivo is demonstrated, through the recognition of lipid phase-separation by triglyceride lipases. This exemplified how liposome morphology and composition can determine nanoparticle-protein interactions. Here, the lipase-induced compositional and morphological changes of phase-separated liposomes-which bear a lipid droplet in their bilayer- are investigated, and the mechanism upon whichlipases recognize and bind to the particles is unravelled. The selective lipolytic degradation of the phase-separated lipid droplet is observed, while nanoparticle integrity remains intact. Next, the Tryptophan-rich loop of the lipase is identified as the region with which the enzymes bind to the particles. This preferential binding is due to lipid packing defects induced on the liposome surface by phase separation. In parallel, the existing knowledge that phase separation leads to in vivo selectivity, is utilized to generate phase-separated mRNA-LNPs that target cell-subsets in zebrafish embryos, with subsequent mRNA delivery and protein expression. Together, these findings can expand the current knowledge on selective nanoparticle-protein communications and in vivo behavior, aspects that will assist to gain control of lipid-based nanoparticles.

Aspects of the alternative host response to methacrylic acid containing biomaterials.

Methacrylic acid (MAA)-based biomaterials promote a vascularized host response without the addition of exogenous factors such as cells or growth factors. We presume that materials containing MAA favor an alternative foreign body response, rather than the conventional fibrotic response. Here, we characterize selected aspects of the response to two different forms of MAA-a coating, which can be used to prevascularize the subcutaneous tissue for subsequent therapeutic cell delivery or an injectable hydrogel, which can be used to vascularize and deliver cells simultaneously. We show that the MAA-coating quickly vascularized the subcutaneous space compared to an uncoated silicone tube, and after 14 days of prevascularization, the tissue surrounding the MAA-coated tube presented fewer immune cells than the uncoated control. We also compared the host response to a MAA-PEG (polyethylene glycol) hydrogel at day 1, with pancreatic islets in immune-compromised SCID/bg mice and immune-competent Balb/c mice. The Balb/c mouse presented a more inflammatory response with increased IFN-γ production as compared to the SCID/bg. Together with previously published data, this work contributes to a further understanding of tissue responses to a biomaterial in different forms as used for cell delivery.

Risk of Preterm Birth among Secundiparas with a Previous Cesarean due to a Failed Vacuum Delivery

Background: Studies have found an association between second-stage cesarean sections (SSCSs) and subsequent preterm birth (PTB). We aimed to evaluate if secundiparas with previous second-stage cesarean sections due to a failed vacuum delivery (SSCS-F-VD) are associated with PTB in the subsequent delivery compared with secundiparas with previous spontaneous vaginal birth (SVB) at term. A secondary aim was to compare this association with secundiparas with a previous SSCS at term. Methods: A historical, prospective, longitudinal cohort study was conducted in a large tertiary university hospital between 2006 and 2019. Matched mothers who experienced first and second births at the indexed hospital, excluding those with a previous miscarriage or multiple pregnancy in either the first or second birth were grouped based on the mode of delivery and gestational week of the first birth. Results: Parturients with term SVB and term SSCSs were less likely to experience PTB in the following delivery compared with those who underwent an SSCS-F-VD, with 496/14,551 (3.4%) versus 6/160 (3.8%) versus 5/61 (8.2%), respectively, at p < 0.001. A logistic regression model revealed that secundiparas with previous SSCS-F-VD had an association with PTB in the following delivery compared with term SVB, with an OR of 2.756 (1.097; 6.922, p = 0.031). Conclusion: Previous SSCS-F-VD is associated with PTB in the following delivery, offering valuable insights for pregnancy management and patient counseling.

Hepatitis C and obstetrical morbidity in a substance use disorder clinic: a role for telemedicine?

Hepatitis C infection often co-occurs with substance use disorders in pregnancy. Accessing hepatitis C treatment is challenging because of loss to follow-up in the postpartum period, attributable to social and financial barriers to care. Telemedicine has been explored as a means of increasing routine postpartum care, but the potential impact on retention in and completion of care for postpartum hepatitis C has not been assessed. This study aimed to evaluate the impact of hepatitis C on obstetrical morbidity in a substance use disorder-specific prenatal clinic, and the effect of Infectious Disease telemedicine consultation on subsequent treatment delivery. We performed a retrospective cohort study of all patients in our substance use disorder prenatal clinic from June 2018 to February 2023. Telemedicine consults for hepatitis C diagnoses began in March 2020 and included electronic chart review by Infectious Disease when patients were unable to be seen. Our primary outcome was composite obstetrical morbidity (preterm birth, preeclampsia, fetal growth restriction, fetal anomaly, abruption, postpartum hemorrhage, or chorioamnionitis) compared between patients with and without active hepatitis C. We additionally evaluated rates of completed referral and initiation of hepatitis C treatment before and after implementation of telemedicine consult. A total of 224 patients were included. Of the 222 patients who underwent screening, 71 (32%) were positive for active hepatitis C. Compared with patients without hepatitis C, a higher proportion of patients with hepatitis C were White (80% vs 58%; P=.02), had a history of amphetamine use (61% vs 32%; P<.01), injection drug use (72% vs 38%; P<.01), or overdose (56% vs 29%; P<.01), and were on methadone (37% vs 18%; P<.01). There was no difference in the primary outcome of composite obstetrical morbidity. The rate of hepatitis C diagnosis was not statistically significantly different between the pre- and posttelemedicine cohorts (N=29 [41%], N=42 [27%]), and demographics of hepatitis C virus-positive patients were similar, with most being unemployed, single, and publicly insured. A lower proportion of patients in the posttelemedicine group reported heroin use compared with the pretelemedicine cohort (62% vs 90%; P=.013). After implementation of telemedicine, patients were more likely to attend the visit (19% vs 44%; P=.03), and positive patients were much more likely to receive treatment (14% vs 57%; P<.01); 100% of visits in the posttelemedicine group occurred via telemedicine. There were 7 patients who were prescribed treatment by their obstetrician after chart review by Infectious Disease. Patients with and without hepatitis C had similar maternal and neonatal outcomes, with multiple indicators of social and financial vulnerability. Telemedicine Infectious Disease consult was associated with increased follow-up and hepatitis C treatment, and obstetricians were able to directly prescribe. Because patients with substance use disorders and hepatitis C may have increased barriers to care, telemedicine may represent an opportunity for intervention.

A prospective study of antepartum anxiety screening in patients with and without a history of spontaneous preterm birth

Maternal stress has been identified as one of the most common clinical phenotypes associated with preterm birth. The American College of Obstetricians and Gynecologists recommends anxiety screening at least once in the perinatal period. The prevalence of perinatal anxiety is challenged by the absence of formalized screening protocols and underreporting in high-risk populations, such as those with a history of adverse pregnancy outcomes. This study administered a validated anxiety screening tool in a cohort of patients with and without a previous spontaneous preterm birth and compared differences in score and rate of a positive screen between groups. Moreover, this study evaluated perinatal outcomes associated with a positive screen and described a referral protocol involving evaluation by a perinatal mental health counselor and clinical diagnoses. A hypothesis was made that patients with a previous history of spontaneous preterm birth would have higher self-reported anxiety symptoms than controls and that those with recurrent preterm delivery at <35 weeks of gestation would have the highest anxiety screening scores. This was a prospective observational cohort study administering the Generalized Anxiety Disorder 7-item screen to patients enrolled in 2 prenatal care clinics at our institution. The preterm birth cohort consisted of patients with a history of spontaneous preterm labor, premature rupture of membranes, or cervical insufficiency compared with the control cohort without this history. Screening was initiated at entry to prenatal care or referral to our high-risk obstetrical clinic. The inclusion criteria included English- or Spanish-speaking patients and singleton pregnancy, and the exclusion criteria included pregnancies complicated by a major congenital anomaly, enrollment after 34 weeks of gestation, delivery at <20 weeks of gestation, and incomplete delivery data. Referral to a mental health counselor was offered to those with a Generalized Anxiety Disorder 7-item screen score of ≥10. Perinatal outcomes as a comparison between the Generalized Anxiety Disorder 7-item screen-positive group and Generalized Anxiety Disorder 7-item screen-negative group were performed with statistical methods, including the Student t test, chi-square test, and Wilcoxon rank-sum test, with a P value of <.05 to determine significance. Between September 2020 and December 2021, 1349 participants were analyzed, with 143 patients (11%) in the previous preterm birth cohort and 1206 (89%) patients in the control cohort. Patients with a history of preterm birth and subsequent delivery at ≤35 weeks of gestation in the study pregnancy had significantly higher Generalized Anxiety Disorder 7-item screen scores than controls with delivery after 35 weeks of gestation (median score: 4 [interquartile range, 1-9] vs 2 [interquartile range, 0-6], respectively; P=.006). Overall, 187 participants (14%) screened positive with significantly higher rates in the previous preterm birth group than in the control group (20% vs 13%; P=.036). Of note, 117 patients (63%) accepted a referral, and 32 patients (17%) with a positive screen were diagnosed with a perinatal mood disorder. Patients with recurrent preterm birth have higher self-reported anxiety using the Generalized Anxiety Disorder 7-item screen than controls. Of those with a positive screen, 17% were diagnosed with a perinatal mood disorder.

Laparoscopic Management of Spontaneous Heterotopic Pregnancy with Abdominal Implantation and Subsequent Full-Term Vaginal Delivery

Laparoscopic Management of Spontaneous Heterotopic Pregnancy with Abdominal Implantation and Subsequent Full-Term Vaginal Delivery

A novel approach to the manufacture of dissolving microneedles arrays using aerosol jet printing

Despite much research over the last few decades, microneedle arrays for the transdermal delivery of drugs have failed to live up to their initial promise. This may be changing however as companies close in on the commercial delivery of vaccines via this technology. These breakthroughs will undoubtably increase the interest in the use of microneedles arrays for the delivery of biopharmaceuticals but will also drive research into the development of scalable manufacturing processes for their fabrication. While 3D printing is an exciting development in this field, conventional Additive Manufacturing (AM) techniques are unsuitable for biopharmaceuticals due to the harsh processing conditions which can cause degradation of the active ingredient.In this paper we report the first use of Aerosol Jet Printing (AJP) as an AM technique for the fabrication of dissolving microneedle arrays. A formulation of poly(vinyl pyrrolidone), trehalose and glycerol dissolved in water was prepared and characterised. The formulation was aerosolised using ultrasonication and deposited onto a silicon substrate. Critical process parameters such as Computer Aided Design (CAD) design, flow rate, temperature, print speed and focussing ratio were studied to determine their impact on the microneedle quality attributes. 4 × 4 microneedle arrays were printed, with needle heights > 500 µm achieved with print times of 30 mins or less. The resulting needles had sufficient strength and sharpness to penetrate porcine skin samples. Importantly, the microneedles can be fabricated under benign conditions which should be suitable for the processing and subsequent delivery of biopharmaceuticals across the skin.

Association of Parity and Previous Birth Outcome With Brachial Plexus Birth Injury Risk.

To evaluate the association of maternal delivery history with a brachial plexus birth injury risk in subsequent deliveries and to estimate the effect of subsequent delivery method on brachial plexus birth injury risk. We conducted a retrospective cohort study of all live-birth deliveries occurring in California-licensed hospitals from 1996 to 2012. The primary outcome was recurrent brachial plexus birth injury in a subsequent pregnancy. The exposure was delivery history (parity, shoulder dystocia in a previous delivery, or previously delivering a neonate with brachial plexus birth injury). Multiple logistic regression was used to model adjusted associations of delivery history with brachial plexus birth injury in a subsequent pregnancy. The adjusted risk and adjusted risk difference for brachial plexus birth injury between vaginal and cesarean deliveries in subsequent pregnancies were determined, stratified by delivery history, and the number of cesarean deliveries needed to prevent one brachial plexus birth injury was determined. Of 6,286,324 neonates delivered by 4,104,825 individuals, 7,762 (0.12%) were diagnosed with a brachial plexus birth injury. Higher parity was associated with a 5.7% decrease in brachial plexus birth injury risk with each subsequent delivery (adjusted odds ratio [aOR] 0.94, 95% CI 0.92-0.97). Shoulder dystocia or brachial plexus birth injury in a previous delivery was associated with fivefold (0.58% vs 0.11%, aOR 5.39, 95% CI 4.10-7.08) and 17-fold (1.58% vs 0.11%, aOR 17.22, 95% CI 13.31-22.27) increases in brachial plexus birth injury risk, respectively. Among individuals with a history of delivering a neonate with a brachial plexus birth injury, cesarean delivery was associated with a 73.0% decrease in brachial plexus birth injury risk (0.60% vs 2.21%, aOR 0.27, 95% CI 0.13-0.55) compared with an 87.9% decrease in brachial plexus birth injury risk (0.02% vs 0.15%, aOR 0.12, 95% CI 0.10-0.15) in individuals without this history. Among individuals with a history of brachial plexus birth injury, 48.1 cesarean deliveries are needed to prevent one brachial plexus birth injury. Parity, previous shoulder dystocia, and previously delivering a neonate with brachial plexus birth injury are associated with future brachial plexus birth injury risk. These factors are identifiable prenatally and can inform discussions with pregnant individuals regarding brachial plexus birth injury risk and planned mode of delivery.

Development of an oral nanovaccine for dogs against Echinococcus granulosus

Dogs are the main source of animal and human cystic echinococcosis caused by the Cestode parasite Echinococcus granulosus. Dog vaccination seems to be a good strategy to control this parasitic disease. Here we present the development of a polymeric nanoparticle-based oral vaccine for dogs against Echinococcus granulosus delivered in enteric-coated capsules. To achieve our target, we encapsulated two recombinant antigens into biodegradable polymeric nanoparticles in the presence of Monophosphoryl lipid A as an adjuvant to ensure efficient delivery and activation of a protective mucosal immune response. The formulated delivery system showed a nanoparticle size less than 200 nm with more than 80 % antigen encapsulation efficiency and conserved integrity and immunogenicity. The nanoparticle surface was coated with chitosan to enhance adhesion to the gut mucosa and a subsequent antigen delivery. Chitosan-coated nanoparticles showed a higher cell internalization in murine macrophages and dendritic cells as well as a higher penetration into Caco-2 cells in vitro. Antigen-loaded nanoparticles were freeze-dried and enteric-coated capsules were filled with the obtained powder. The obtained results show a promising nanoparticles delivery system for oral vaccination.

Risk of recurrent red-cell transfusion in delivery: A nationwide longitudinal study.

To investigate the risk of recurrent maternal red-cell transfusion in delivery. Nationwide long-standing retrospective cohort study. Swedish medical birth register. All registered births from 2000 to 2017 in Sweden. We included all women with between one and three consecutive registered births from 22 weeks of gestation onwards and all maternal red-cell transfusions in the peripartum period within the defined period of study. Information on gestational and non-gestational comorbidity was collected and we identified any female siblings. In our analyses we compared the risk of red-cell transfusion in delivery in relation to transfusion history and gestational and non-gestational comorbidity. Maternal peripartum red-cell transfusion, defined as a recorded transfusion in the period from 1 day before and 7 days after delivery. We included 825 451 women with a total 1 419 909 deliveries, including 786 097 (55.4%) first, 511 398 (36.0%) second and 122 414 (8.6%) third deliveries. Of women with previous obestric transfusion, 8.7% were transfused in a second delivery, compared with 1.7% of women without transfusion or diagnosis of haemorrhage. A previous diagnosis of haemorrhage did not affect the odds ratio of transfusion recurrence. Among women who were transfused in their first two deliveries, 15.5% were transfused in third delivery, corresponding to an 11-fold increase, compared with non-transfused women (adjusted odds ratio aOR 11.5, 95% CI 7.9-16.6). Women with a sister transfused in delivery were at increased risk of transfusion in a second delivery (aOR 1.8, 95% CI 1.6-2.1). Women with previous red-cell transfusion are at an increased risk of red-cell transfusion in a subsequent delivery, compared with women without a history of red-cell transfusion.

Pregnancy and spontaneous cervical artery dissection: A propensity-matched retrospective cohort study

ObjectivesWe hypothesized that pregnant women would have an increased risk of spontaneous cervical artery dissection (sCeAD) affecting the carotid or vertebral arteries over one-year follow-up after the first trimester ultrasound compared to matched non-pregnant controls. Materials and MethodsWe queried a United States research network (TriNetX, Inc.) of de-identified medical records of >111 million patients, with data spanning 2008-2023. We included women aged ≥18 and excluded those with trauma and conditions potentially causative of sCeAD. Women were divided into cohorts based on a1 first trimester ultrasound and subsequent labor, delivery, or full-term pregnancy, or2 gynecological examination and no pregnancy. We used propensity matching to control for variables associated with sCeAD and calculated the risk ratio (RR) of sCeAD occurring over one-year follow-up from the index date of ultrasound or gynecological exam. ResultsAfter matching, the incidence rate of sCeAD in the pregnancy cohort was 8.0 (95% CI: 8.0-8.1) per 100,000 person-years, compared to 3.9 (95% CI: 3.9-3.9) per 100,000 person-years in the non-pregnancy cohort, yielding an RR (95% CI) of 2.06 (1.17-3.61; P= .0104). A cumulative incidence graph suggested that most cases of sCeAD in the pregnancy cohort occurred during pregnancy rather than the postpartum period. ConclusionsOur findings demonstrate that women have a twofold increased risk of sCeAD during pregnancy and the postpartum period compared to non-pregnant women. Further research is needed to determine whether maternal comorbidities such as preeclampsia account for these findings, and clarify when sCeAD occurs in relation to pregnancy or the postpartum period.

Projecting future prolapse outcomes with induction of labor at 39 weeks: a decision analysis.

In 2018, the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management) concluded that routine induction of labor (IOL) at 39 weeks gestation decreases cesarean delivery risk, with slightly lighter birthweight infants. We debated whether routine IOL would improve, worsen, or not change POP risk compared with expectant management (EM). We constructed a decision analysis model with a lifetime horizon where nulliparous women reaching 39 weeks underwent IOL or EM. Subsequent vaginal versus cesarean delivery varied based on prior deliveries for up to four births. Subsequent delivery prior to 39 weeks and distribution of gestational age, birthweight, and delivery mode between 24 and 39 weeks was modeled from national data. We modeled increased POP risk with increasing vaginal parity, forceps delivery, and weight of largest infant delivered vaginally, accounting for differential infant weights in each strategy. IOL and EM have similar population-wide POP risk (15.9% and 15.7% respectively). Among women with only spontaneous vaginal deliveries that reached 39 weeks or beyond, the prevalence of POP was 20% after one delivery and 29% after four deliveries, with no difference between groups. The cesarean rate was lower with IOL (27.8% versus 29.8%). Sensitivity analysis revealed no meaningful thresholds among the variables, supporting model robustness. While routine induction of labor at 39 weeks results in a meaningfully higher vaginal delivery rate, there was no increase in POP, possibly due to the protective effect of lower birthweight.

A Novel Approach to Predicting Early Pregnancy Outcomes Dynamically in a Prospective Cohort Using Repeated Ultrasound and Serum Biomarkers

This study aimed to develop a dynamic model for predicting outcome during the first trimester of pregnancy using baseline demographic data and serially collected blood samples and transvaginal sonographies. A prospective cohort of 203 unselected women with an assumed healthy pregnancy of < 8 weeks’ gestation was followed fortnightly from 4–14 weeks’ gestation until either miscarriage or confirmed first trimester viability. The main outcome was development of a model to predict outcome from gestational age-dependent hazard ratios using both baseline and updated serial data from each visit. Secondary outcomes were descriptions of risk factors for miscarriage. The results showed that 18% of the women experienced miscarriages. A fetal heart rate detected before 8 weeks’ gestation indicated a 90% (95% CI 85–95%) chance of subsequent delivery. Maternal age (≥ 35 years), insufficient crown-rump-length (CRL) and mean gestational sac diameter (MSD) development, and presence of bleeding increased the risk of miscarriage. Serum biomarkers, including hCG, progesterone, and estradiol, were found to impact the risk of miscarriage with estradiol as the most important. The best model to predict miscarriage was a combination of maternal age, vaginal bleeding, CRL, and hCG. The second-best model was the sonography-absent model of maternal age, bleeding, hCG, and estradiol. This study suggests that combining maternal age, and evolving data from hCG, estradiol, CRL, and bleeding could be used to predict fetal outcome during the first trimester of pregnancy.Trial registration ClinicalTrials.gov identifier: NCT02761772.

Extracellular vesicle‐mediated protein delivery to the liver

AbstractExtracellular vesicles (EVs) are nanoscale particles that facilitate intercellular communication. They are regarded as a promising natural drug delivery system for transporting and delivering bioactive macromolecules to target cells. Recently, researchers have engineered EVs with FKBP12/FRB heterodimerization domains that interact with rapamycin to load and deliver exogenous proteins for both in vitro and in vivo applications. In this study, we examined the tissue distribution of EVs using near‐infrared fluorescent imaging. We evaluated the effectiveness of EV‐mediated delivery of Cre recombinase specifically to hepatocytes in the livers of Ai9 Cre‐loxP reporter mice. Intravenous injection resulted in more efficient Cre protein delivery to the liver than intraperitoneal injections. Depleting liver‐resident macrophages with clodronate‐encapsulated liposome pre‐treatment did not enhance EV‐mediated Cre delivery to hepatocytes. Moreover, we demonstrated that multiple intravenous injections of Cre‐EVs facilitated functional Cre delivery to hepatocytes. To the best of our knowledge, this is the first study to simultaneously investigate the tissue distribution of FKBP12/FRB‐engineered EVs and their subsequent intracellular protein delivery in Ai9 Cre‐loxP reporter mice. These insights can inform preclinical research and contribute to developing next‐generation EV‐based platforms for delivering therapeutic proteins or genome editing technologies targeting the liver.

How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors.

The lack of effective chemotherapeutic agents for the treatment of brain tumors is a serious unmet medical need. This can be attributed, in part, to inadequate delivery through the blood-brain barrier (BBB) and the tumor-cell barrier, both of which have active efflux transporters that can restrict the transport of many potentially effective agents for both primary and metastatic brain tumors. This review briefly summarizes the components and function of the normal BBB with respect to drug penetration into the brain and the alterations in the BBB due to brain tumor that could influence drug delivery. Depending on what is rate-limiting a compound's distribution, the limited permeability across the BBB and the subsequent delivery into the tumor cell can be greatly influenced by efflux transporters and these are discussed in some detail. Given these complexities, it is necessary to quantify the extent of brain distribution of the active (unbound) drug to compare across compounds and to inform potential for use against brain tumors. In this regard, the metric, Kp,uu, a brain-to-plasma unbound partition coefficient, is examined and its current use is discussed. However, the extent of active drug delivery is not the only determinant of effective therapy. In addition to Kp,uu, drug potency is an important parameter that should be considered alongside drug delivery in drug discovery and development processes. In other words, to answer the question - How much is enough? - one must consider how much can be delivered with how much needs to be delivered.

Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus.

Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and manypatients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-β29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that ismore effective than placebo throughout the meal period; however, compared withan active comparator insulin aspart, the post-prandial control ismore effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.