Activity restriction and risk of adverse pregnancy outcomes.

BACKGROUND: Activity restriction is a common recommendation given to patients during pregnancy for various indications, despite lack of definitive data showing improvements in pregnancy outcomes. OBJECTIVE: To determine if activity restriction (AR) in pregnancy is associated with decreased odds of adverse pregnancy outcomes (APOs). STUDY DESIGN: Secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) prospective cohort. Nulliparous singletons were followed at 8 sites from October 2010 - September 2013. Demographic and clinical data were collected at 4 timepoints, and participants were surveyed about AR recommendations at 22w0d-29w6d and delivery. We excluded participants missing data on AR and age. Participants were grouped according to history of AR, and APOs included: gestational hypertension (gHTN), preeclampsia/eclampsia, preterm birth (PTB), and small for gestational age (SGA) neonate. Associations between AR and APOs were examined using uni- and multivariable logistic regression models adjusting for a priori identified APO risk factors. RESULTS: Of 10,038 nuMoM2b participants, 9,312 met inclusion criteria and 1,386 (14.9%) were recommended AR; participants identifying as Black [aOR 0.81 (95% CI 0.68-0.98)] or Hispanic [aOR 0.73 (95% CI 0.61-0.87)] were less likely to be placed on AR when compared to those identifying as White. Overall, 3,197 (34.3%) experienced at least one APO [717 (51.7%) of participants with AR compared to 2,480 (31.3%) participants without AR]. After adjustment for baseline differences, the AR group had increased odds of gHTN [aOR 1.61 (95% CI 1.35-1.92)], preeclampsia/eclampsia [aOR 2.52 (95% CI 2.06-3.09)] and iatrogenic and spontaneous PTB [aOR 2.98 (95% CI 2.41-3.69)], but not delivery of an SGA neonate. CONCLUSION: AR in pregnancy was independently associated with increased odds of hypertensive disorders of pregnancy and PTB, but future prospective work is needed to determine potential causality. Further, participants identifying as Black or Hispanic were significantly less likely to be recommended AR compared to those identifying as White. While AR is not an evidence-based practice, these findings suggest bias may impact which patients receive advice to limit activity in pregnancy.

Perinatal outcomes according to umbilical artery Doppler assessment among fetuses with congenital heart disease.

PURPOSE: To evaluate a cohort of fetuses with congenital heart disease (CHD) who underwent serial umbilical artery (UA) Doppler surveillance and assess perinatal outcome according to UA Doppler assessment. METHODS: A retrospective cohort study of singleton fetuses with CHD at a single academic center was performed between 2018 and 2020. Fetuses with a chromosomal abnormality or growth restriction were excluded. We compared fetuses with normal versus abnormal UA Doppler assessment at any time in pregnancy. Abnormal UA Doppler assessment was defined as decreased end diastolic flow, determined by an elevated systolic/diastolic ratio >95th percentile for gestational age, or absent/reversed end diastolic flow. Logistic regression assessed the odds of fetuses with CHD and abnormal UA Doppler assessment having a composite adverse perinatal (defined as fetal, neonatal, or infant death), adjusting for relevant covariates. RESULTS: We identified a cohort of 171 fetuses with CHD that met inclusion criteria. Of these, 154 (90%) had normal UA Doppler assessment and 17 (10%) had abnormal UA Doppler assessment throughout pregnancy. Maternal characteristics did not differ between groups except for maternal race and history of preeclampsia. There was no statistically significant difference in primary outcome between groups [14% (21/154) of fetuses with normal UA Doppler assessment had an adverse perinatal outcome compared to 24% (4/17) of those with abnormal UA Doppler assessment, p = 0.28]. CONCLUSION: UA Doppler assessment is unlikely to predict adverse perinatal outcome in normally grown, euploid singleton fetuses with CHD.

Association between acceptance of routine pregnancy vaccinations and COVID-19 vaccine uptake in pregnant patients.

OBJECTIVE: COVID-19 vaccination is a key approach to reduce morbidity and mortality in pregnant patients and their newborns. Anti-vaccine sentiment has recently increased with unclear impact on pregnant patients. We examined the association between acceptance of tetanus-diphtheria-acellular pertussis (Tdap) and influenza vaccines, considered to be routine pregnancy vaccines, and COVID-19 vaccine acceptance. Secondarily, we identified other predictors of COVID-19 vaccine uptake and described pregnancy outcomes in patients who were and were not vaccinated during pregnancy. METHODS: A retrospective cohort study of all patients who delivered at a single site from December 2020 - March 2022. Demographic, pregnancy, neonatal, and vaccination data were abstracted from the electronic medical record, which imports vaccine history from the California Immunization Registry. The relationship between influenza and Tdap vaccine acceptance, other baseline characteristics, and COVID-19 vaccine uptake was assessed using univariable and multivariable regression analysis. RESULTS: Of the 7857 patients who delivered during the study period, 4410 (56.1%) accepted the COVID-19 vaccine. Of those who received the COVID-19 vaccine, 3363 (97.6%) and 3049 (88.5%) received influenza and Tdap vaccines, respectively. Patients were more likely to receive the COVID-19 vaccine if they had advanced maternal age, obesity, Asian race, and private insurance. After adjustment for baseline differences, COVID vaccine acceptance was associated with receipt of Tdap (aOR 2.10, 95% CI 1.90-2.33) and influenza vaccines (aOR 2.83, 95% CI 2.55-3.14). There were no differences in preterm birth, low birthweight, and NICU admission between patients who received and did not receive the COVID-19 vaccine. CONCLUSION: Patients were more likely to accept COVID-19 vaccination if they received Tdap or influenza vaccinations. Older age, obesity, Asian race, and private insurance were independent predictors of vaccine uptake. Disparities in COVID-19 vaccination uptake bear further exploration to guide efforts in equitable and widespread vaccine distribution.

Laminar flow-assisted synthesis of amorphous ZIF-8-based nano-motor with enhanced transmigration for photothermal cancer therapy.

Because of their biocompatibility, there are promising applications in various fields for enzyme-powered nano-motors. However, enzymes can undergo denaturation under harsh conditions. Here, we report the flow-assisted synthesis of an enzyme-based amorphous ZIF-8 nano-motor (A-motor; Pdop@urease@aZIF-8) for enhanced movement and protection of polydopamine and enzymes. Multiple laminar flow types with varied input ratios effectively entrapped enzymes into amorphous ZIF-8 shells in a serial flow with a momentary difference. The obtained A-motor exhibited superior enzymatic activity and photothermal ablation properties with excellent durability due to the protection the amorphous shell offers from the external environment. Furthermore, in the bio-mimic 2D membrane model, the enhanced mobility of the A-motor afforded high transmigration (>80%), which had a powerful effect on bladder cancer cell ablation via photothermal therapy. This work envisages that the rapid flow approach will facilitate scalable manufacturing of the nano-motors under low stress to vulnerable biomolecules, which would be extended to nano-biomedical applications in various body environments.

Rapid Flow Synthesis of a Biomimetic Carbonate Apatite as an Effective Drug Carrier.

A facile synthesis of apatite nanocrystals analogous to bioapatites with increased biocompatibility and biodegradability can remedy the shortcomings of the widely applied synthetic hydroxyapatite (HAp) for bone defect treatment. Here, we propose an expeditious synthesis method to develop a biomimetic B-type carbonate apatite (CAp) with a simple capillary microfluidic device at room temperature. The process not only eliminates fluctuations with the addition of carbonate but also produces safe CAp drug carriers through simultaneous alendronate incorporation to the CAp structure. CAp displayed superior mineralization on osteoblast-like MG-63 cells when compared with HAp and HAp drug carriers that were produced using identical methods. Furthermore, alendronate-incorporated CAp drug carriers potentially displayed higher cancer cell suppression when applied to breast cancer cells attached to the bone tissue model, which signifies enhanced cancer metastasis to bone suppression due to the likelihood of increased alendronate release of CAp owing to its faster dissolution. Overall, our results may provide promising opportunities for enhanced clinical CAp application for bone defect treatment, particularly for bone loss and cancer to bone metastasis.

Cytocompatible asymmetrical coating for Janus carrier synthesis through capillary wetting and ascending.

Despite the successful implementation of elegant strategies for the fabrication of Janus microstructures, two critical factors have limited the applicability of most techniques for the partial modification of living cell surfaces: harsh conditions that could disintegrate cells, and the lack of an effective route to accomplish a mild modification for living cells. In this study, an expeditious synthesis, named lower-half occupation by capillary ascended liquids (LOCAL), is proposed for the fabrication of asymmetrical structures surrounding not only microbeads but also both living adherent and buoyant mammalian cells. The microbeads or living cells are safely supported and trapped on the apical sides of a micropillar array, which prevents them from contacting the bottom substrate. As the coating agents further transfer and contact the trapped particles through interpillar capillary flow, the autonomous capillary ascending coats the free bottom surfaces of the target particles within 2 min, with significantly small quantities of coating agents. The self-assembled architectures of the cells demonstrate thoroughly maintained cell viability, highlighting the potential of the LOCAL method as a desirable alternative to the widely applied state-of-art methods for developing Janus beads and Janus cells.

Rapid Single-Step Growth of MOF Exoskeleton on Mammalian Cells for Enhanced Cytoprotection.

Mammalian cells are promising agents for cell therapy, diagnostics, and drug delivery. For full utilization of the cells, development of an exoskeleton may be beneficial to protecting the cells against the environmental stresses and cytotoxins to which they are susceptible. We report here a rapid single-step method for growing metal-organic framework (MOF) exoskeletons on a mammalian cell surface under cytocompatible conditions. The MOF exoskeleton coating on the mammalian cells was developed via a one-pot biomimetic mineralization process. With the exoskeleton on, the individual cells were successfully protected against cell protease (i.e., Proteinase K), whereas smaller-sized nutrient transport across the exoskeleton was maintained. Moreover, vital cellular activities mediated by transmembrane GLUT transporter proteins were also unaffected by the MOF exoskeleton formation on the cell surfaces. Altogether, this ability to control the access of specific molecules to a single cell through the porous exoskeleton, along with the cytoprotection provided, should be valuable for biomedical applications of mammalian cells.

Accuracy of estimated fetal weight assessment in fetuses with abdominal wall defects.

BACKGROUND: Gastroschisis and omphalocele are congenital abdominal wall defects in which the bowel and other abdominal contents extrude from the fetal abdominal cavity. Standard formulas for estimated fetal weight using ultrasound include fetal abdominal circumference measurement and have a range of error of approximately 10%. It is unknown whether the accuracy of estimated fetal weight assessment is compromised in fetuses with abdominal wall defects because of the extrusion of abdominal contents. OBJECTIVE: This study aimed to assess the accuracy of standard estimated fetal weight assessment in fetuses with abdominal wall defects by comparing prenatal assessment of fetal weight with actual birthweight. STUDY DESIGN: A retrospective cohort study of fetuses diagnosed with gastroschisis or omphalocele was performed at a single center from 2012 to 2018. Fetuses with additional anomalies or confirmed chromosome abnormalities were excluded. Estimated fetal weight was calculated using the Hadlock formula. Published estimates of fetal growth rate were used to establish a projected estimated fetal weight at birth from the final growth ultrasound, and the percent difference between projected estimated fetal weight at birth and actual birthweight was calculated. The Wilcoxon rank-sum test was used to examine the difference between projected estimated fetal weight and actual birthweight. RESULTS: We had complete data for 112 fetuses with abdominal wall defects, including 85 with gastroschisis and 27 with omphalocele. The median (interquartile range) projected estimated fetal weight was similar to median birthweight, at 2283 g (interquartile range, 2000-2810) and 2306 g (interquartile range, 1991-264), respectively, which did not represent a statistically significant difference between projected estimated fetal weight and actual birthweight (P=.32). The median percent error was 6.8 (3.1-12.8). In addition, we did not find any statistical difference between projected estimated fetal weight and actual birthweight in patients with gastroschisis (P=.52) or omphalocele (P=.35) individually. Estimated fetal weight was underestimated in most cases (n=68 [60.7%]). CONCLUSION: In fetuses with abdominal wall defects, standard measurement of fetal weight shows an accuracy that is at least comparable with previously established margins of error for ultrasound assessment of fetal weight. Standard estimated fetal weight assessment remains an appropriate method of estimating fetal weight in these fetuses.

Interwoven MOF-Coated Janus Cells as a Novel Carrier of Toxic Proteins.

Two major issues in cell-mediated drug delivery systems (c-DDS) are the availability of free cell surfaces for the binding of the cells to the target or to their microenvironment and internalization of the cytotoxic drug. In this study, the Janus structure, MOF nanoparticles, and tannic acid (TA) are utilized to address these issues. Janus carrier cells coated with metal-organic frameworks (MOFs) are produced by asymmetrically immobilizing the nanoparticles of a MOF based on zinc with cytotoxic enzymes that are internally encapsulated on the surface of carrier cells. By maintaining the biological and structural features of regular living cells, the MOF-coated Janus cells developed in the present study preserve the intrinsic binding capacity of the cells to their microenvironment. Interconnected MOFs loaded onto the other face of the Janus cells cannot penetrate the cell. Therefore, the carrier cells are protected from the cytotoxic drug contained in MOFs. These MOF-Janus carrier cells are demonstrated to successfully eliminate three-dimensional (3D) tumor spheroids when a chemotherapeutic protein of proteinase K is released from the MOF nanoparticles in an acid environment. The ease with which the MOF-Janus carrier cells are prepared (in 15 min), and the ability to carry a variety of enzymes and even multiple ones should make the developed system attractive as a general platform for drug delivery in various applications, including combination therapy.

Enhanced discharge counseling to reduce outpatient opioid use after cesarean delivery: a randomized clinical trial.

BACKGROUND: Strategies to curb overprescribing have focused primarily on the prescriber as the point of intervention. Less is known about how to empower patients to use fewer opioids and decrease the quantity of leftover opioids. Previous studies in nonobstetrical populations suggest that patient counseling about appropriate opioid use improves disposal of unused opioids and overall knowledge about opioid use. Less is known about whether counseling reduces opioid use after hospital discharge. OBJECTIVE: This study examines whether enhanced discharge counseling on optimal analgesic use after cesarean delivery reduces opioid use and improves proper disposal of unused opioids and opioid use knowledge after hospital discharge. STUDY DESIGN: Women who underwent an uncomplicated cesarean delivery were randomized to enhanced counseling on optimal analgesic use or usual care. Enhanced counseling addressed the following 4 points: (1) pain is normal after cesarean delivery; (2) scheduled ibuprofen should be taken to maintain baseline pain control; (3) opioids should be used sparingly and should be tapered over several days; and (4) all unused opioids should be returned to pharmacy or flushed in a toilet. All participants received 30 tablets of 5 mg hydrocodone-acetaminophen and 30 tablets of 600 mg ibuprofen at discharge. They were contacted 14 days later to determine opioid use and location of leftover opioids and to complete a 10-question analgesic strategies quiz with a score of 1 to 10. We estimated that outcome data on 172 women total would provide an 80% power to detect a 30% reduction in postdischarge opioid use with enhanced counseling. RESULTS: Notably, 79% of eligible women consented to the study and 175 of 196 participants (84 enhanced counseling, 91 usual care) completed the follow-up. Compared with usual care, the enhanced counseling group was more likely to follow recommendations for proper opioid disposal (risk ratio, 2.3; 95% confidence interval, 1.3-3.9). They also scored significantly higher on the analgesic strategies quiz (10 points [interquartile range, 9-10] vs 8 points [interquartile range, 7-9]; P<.001) than the usual care group. Although the enhanced counseling group used less opioids (7.5 tablets [interquartile range, 2-15] vs 10.0 tablets [interquartile range, 2-16]; P=.55) and a smaller proportion of prescribed opioids (25.0% [6.7-50.0] vs 33.3% [6.7-53.3], P=.55) than the usual care group, differences were not statistically significant. There was no statistically significant evidence of interaction between participant education level and any of the study outcomes. CONCLUSION: Enhanced discharge opioid counseling doubled the frequency of participants reporting proper opioid disposal and improved overall knowledge about the risks associated with opioids. This intervention did not decrease opioid use in a population of women with low overall opioid use. These findings highlight possible methods to intervene on the short-term (misuse and diversion) and long-term (persistent opioid use) consequences of overprescribing.

Accuracy of estimated fetal weight assessment in fetuses with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia is a congenital anomaly in which fetal abdominal organs herniate into the thoracic cavity through a diaphragmatic defect, which can impede fetal lung development. Standard formulas for estimated fetal weight include measurement of fetal abdominal circumference, which may be inaccurate in fetuses with congenital diaphragmatic hernia because of displacement of abdominal contents into the thorax. OBJECTIVES: This study aimed to assess the accuracy of standard estimated fetal weight assessment in fetuses with congenital diaphragmatic hernia by comparing prenatal assessment of fetal weight with actual birthweight. STUDY DESIGN: A retrospective cohort study of fetuses diagnosed with congenital diaphragmatic hernia was performed at a single center from 2012 to 2018. Fetuses with multiple anomalies or confirmed chromosome abnormalities were excluded. Estimated fetal weight was calculated using the Hadlock formula. Published estimates of fetal growth rate were used to establish a projected estimated fetal weight at birth from the final growth ultrasound, and the percentage difference between projected estimated fetal weight at birth and actual birthweight was calculated. A Wilcoxan rank-sum test was used to examine the difference between projected estimated fetal weight and birthweight. RESULTS: We had complete data for 77 fetuses with congenital diaphragmatic hernia. The majority (76.6%, 55 of 77) had left-sided congenital diaphragmatic hernia. The median [interquartile range] projected estimated fetal weight was similar to median birthweight, at 3177 g [2691-3568] and 3180 g [2630-3500], respectively, which did not represent a statistically significant difference between projected estimated fetal weight and birthweight (P = .66). The median absolute percentage difference between projected birthweight and actual birthweight was 6.3% [3.2-7.0]. Estimated fetal weight was overall underestimated in a minority of cases (44.2%, 34 of 77). CONCLUSION: In fetuses with a congenital diaphragmatic hernia, standard measurements of fetal estimated fetal weight show accuracy that is at least comparable with previously established margins of error for ultrasound assessment of fetal weight. Standard estimated fetal weight assessment remains an appropriate method of estimating fetal weight in fetuses with congenital diaphragmatic hernia.

Magnetically Actuated SiCN-Based Ceramic Microrobot for Guided Cell Delivery.

A silicon carbonitride (SICN) ceramic microrobot, biocompatible and magnetically activable, is developed for the delivery of viable cells to defective tissue by sequential steps of microstructuring, magnetization, and cell loading. The ceramic carrier of porous cylindrical framework is fabricated by 3D laser lithography using a photocurable preceramic polymer, chemically modified polyvinylsilazane, and subsequent pyrolysis at 600 °C under an inert atmosphere. Magnetic nanoparticles (MNP) are integrated into the surface-modified ceramic carrier by thiol-ene click reaction. Finally, the microrobot is loaded with fibroblast cells, which can be guided by a rotating external magnetic field. The proposed ceramic microrobot is mechanically durable, adequately controllable with external magnetic field, and quite compatible with mammalian cells.

Self-Assembly of Extracellular Vesicle-like Metal-Organic Framework Nanoparticles for Protection and Intracellular Delivery of Biofunctional Proteins.

The intracellular delivery of biofunctional enzymes or therapeutic proteins through systemic administration is of great importance in therapeutic intervention of various diseases. However, current strategies face substantial challenges owing to various biological barriers, including susceptibility to protein degradation and denaturation, poor cellular uptake, and low transduction efficiency into the cytosol. Here, we developed a biomimetic nanoparticle platform for systemic and intracellular delivery of proteins. Through a biocompatible strategy, guest proteins are caged in the matrix of metal-organic frameworks (MOFs) with high efficiency (up to ∼94%) and high loading content up to ∼50 times those achieved by surface conjunction, and the nanoparticles were further decorated with the extracellular vesicle (EV) membrane with an efficiency as high as ∼97%. In vitro and in vivo study manifests that the EV-like nanoparticles can not only protect proteins against protease digestion and evade the immune system clearance but also selectively target homotypic tumor sites and promote tumor cell uptake and autonomous release of the guest protein after internalization. Assisted by biomimetic nanoparticles, intracellular delivery of the bioactive therapeutic protein gelonin significantly inhibits the tumor growth in vivo and increased 14-fold the therapeutic efficacy. Together, our work not only proposes a new concept to construct a biomimetic nanoplatform but also provides a new solution for systemic and intracellular delivery of protein.

A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells.

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis.

Mitochondria-based aircraft carrier enhances in vivo imaging of carbon quantum dots and delivery of anticancer drug.

The application of engineered bacteria-based drug delivery vehicles to treat cancer has been practiced for more than a century. Mitochondria, evolutionarily originated from bacteria, are ubiquitous, semi-autonomous cellular organelles. In this study, we present the first exploration of using mitochondria as a delivery system of carbon quantum dots (CQDs) for in vivo imaging and administration of the anticancer drug doxorubicin (DOX). The results show that mitochondria as carriers are compatible with CQD loading and preserve the optical properties of CQDs. Moreover, the mitochondria delivery system can improve the CQD bio-distribution in organs and prolong the retention time of CQDs after intravenous injection. Furthermore, mitochondria loaded with doxorubicin hydrochloride (Mito-DOX) show an enhanced therapeutic effect compared to free DOX. The mitochondria-based "aircraft" system may be a promising novel therapeutic platform with high potential for biological imaging and drug delivery to fight cancer and other diseases.

Replication of flexible polymer membranes with geometry-controllable nano-apertures via a hierarchical mould-based dewetting.

Membranes with nano-apertures are versatile templates that possess a wide range of electronic, optical and biomedical applications. However, such membranes have been limited to silicon-based inorganic materials to utilize standard semiconductor processes. Here we report a new type of flexible and free-standing polymeric membrane with nano-apertures by exploiting high-wettability difference and geometrical reinforcement via multiscale, multilevel architecture. In the method, polymeric membranes with various pore sizes (50-800 nm) and shapes (dots, lines) are fabricated by a hierarchical mould-based dewetting of ultraviolet-curable resins. In particular, the nano-pores are monolithically integrated on a two-level hierarchical supporting layer, allowing for the rapid (<5 min) and robust formation of multiscale and multilevel nano-apertures over large areas (2 × 2 cm(2)).

Enhanced skin adhesive patch with modulus-tunable composite micropillars.

Modulus-tunable composite micropillars are presented by combining replica molding and selective inking for skin adhesive patch in "ubiquitous"-health diagnostic devices. Inspired from hierarchical hairs in the gecko's toe pad, a simple method is presented to form composite polydimethylsiloxane (PDMS) micropillars that are highly adhesive (∼1.8 N cm(-2) ) and mechanically robust (∼30 cycles).